Skip to main content

X-ray cross-complementing family: the bridge linking DNA damage repair and cancer

Abstract

Genomic instability is a common hallmark of human tumours. As a carrier of genetic information, DNA is constantly threatened by various damaging factors that, if not repaired in time, can affect the transmission of genetic information and lead to cellular carcinogenesis. In response to these threats, cells have evolved a range of DNA damage response mechanisms, including DNA damage repair, to maintain genomic stability. The X-ray repair cross-complementary gene family (XRCC) comprises an important class of DNA damage repair genes that encode proteins that play important roles in DNA single-strand breakage and DNA base damage repair. The dysfunction of the XRCC gene family is associated with the development of various tumours. In the context of tumours, mutations in XRCC and its aberrant expression, result in abnormal DNA damage repair, thus contributing to the malignant progression of tumour cells. In this review, we summarise the significant roles played by XRCC in diverse tumour types. In addition, we discuss the correlation between the XRCC family members and tumour therapeutic sensitivity.

Background

Genomic instability, a hallmark of cancer, ensues from a complex interplay involving DNA damage, tumour-specific flaws in DNA repair, and the inability to halt or impede the cell cycle prior to transmitting damaged DNA to daughter cells [1, 2]. Human DNA is exposed to tens of thousands of instances of damage each day, arising from both endogenous and exogenous factors, such as metabolites, ionising radiation (IR), ultraviolet (UV) light, and DNA damage resulting from replication errors [3,4,5]. Unrepaired DNA damage can significantly elevate the risk of various cancers, including breast, ovarian, prostate, and glioma, among others [6,7,8,9]. To maintain genome stability, cells adopt several measures to repair damaged DNA.

DNA damage repair (DDR) is one of the most critical biological responses in living organisms. The DNA repair pathway is usually a multi-step, nonlinear reaction involving a series of repair factors that work together in a time-series [10]. The DDR system contains five major repair pathways: base excision repair (BER), homologous recombination (HR), mismatch repair (MMR), nucleotide excision repair (NER), and non-homologous end-joining (NHEJ) [11]. Among all types of DNA damage, DNA double-strand breaks (DSB) are the most severe type of damage, and their efficient repair is essential for maintaining genome stability. There are two major DSB repair pathways in eukaryotes: HR and NHEJ [12, 13]. Mutations or aberrant expression of DDR-related genes result in compromised DNA damage repair functions, thereby reducing the capability of cells to repair damages caused by endogenous and exogenous stimuli. This fosters the accumulation of genetic alterations, ultimately leading to tumorigenesis [14]. DNA damage and abnormal DDR function not only contribute to tumorigenesis but also present opportunities and targets for tumour treatment. Many antitumour drugs operate in close association with the DNA damage and repair systems [15].

The DNA repair system is a vast and intricate network closely intertwined with all aspects of life, yet it remains inadequately understood. To date, several repair-related genes have been identified; however, their specific functions are not well understood. Among these, X-ray cross-complementing (XRCC) genes are some of the most studied DNA repair genes, and their abnormal expression has been reported to be associated with the development of various malignancies [16,17,18,19,20,21]. The XRCC gene family comprises 11 main members (XRCC1–11), primarily responsible for maintaining chromosome stability by participating in DNA single-strand break repair [22, 23]. Among them, XRCC1–6 is a recognized member of the XRCC family, highly expressed in various tumour tissues and exhibiting multiple mutations in pan-cancer (Figs. 1 and 2). In addition, they play different biological functions in different cancer types (Table 1). In this review, we comprehensively elucidate the functions of the XRCC gene family in DNA damage repair, delving into their underlying mechanisms, and exploring their significant roles in tumour progression. In addition, we discuss the role of the XRCC gene family in the context of therapeutic sensitivities.

Fig. 1
figure 1

XRCC1-XRCC6 is abnormally expressed in a variety of tumours. The RNA-seq data of the tumours shown in the figure were obtained using The Cancer Genome Atlas (TCGA) database, and the expression levels of XRCC1–6 in tumour tissues and normal tissues were analysed, where the horizontal coordinates represent different genes and the vertical coordinates represent the gene expression distribution. Different colours represent different groups. *p < 0.05, **p < 0.01, ***p < 0.001

Fig. 2
figure 2

Genetic alterations of XRCC1–6 in pan-cancer. Analysis of XRCC1-XRCC6 mutations in pan-cancer using the cBioPortal database (https://www.cbioportal.org/)

Table 1 The list of XRCCs and their biological functions in different cancer types

Structure and biological properties of the XRCC gene family

The XRCC family constitutes an essential group of DNA double-stranded break repair-related genes, responsible for encoding proteins involved in homologous recombination, which is indispensable for maintaining chromosomal stability and accomplishing DNA damage repair [24]. When DNA damage occurs, different XRCC genes participate in distinct DNA damage repair pathways. In the context of double-stranded DNA damage repair, XRCC2, 3, and 11 operate through the HR pathway, whereas XRCC4, 5, 6, and 7 operate through the NHEJ pathway [23]. Notably, among the 11 members of the XRCC family, the probability of XRCC7 (PRKDC), XRCC8, XRCC9 (FANCG), XRCC10, and XRCC11 (BRCA2) belonging to this family remains controversial [22].

XRCC1 is located on chromosome 19q13.2–13.3, exhibits a total length of approximately 33 kb and contains 17 exons [25]. The XRCC1 encodes a protein with three functional domains: the N-terminal domain, the BRCA1 carboxyl-terminal (BRCT) I domain, and the C-terminal BRCT II domain (Fig. 3), which interact with DNA polymerase beta, DNA ligase III, and poly(ADP-ribose) polymerase (PARP) to form a complex that acts as a “scaffolding protein” in the base excision repair process [23]. Human XRCC1 was the first isolated mammalian repair gene reported to be associated with the repair of DNA damage caused by ionising radiation. In 1990, XRCC1 was cloned by Thompson et al. from the gene library of EM9 cells [26]. In EM9 cells, the DNA ligase activity is reduced. Exposure to ionising radiation or ethyl methanesulfonate (EMS) led to impaired DNA strand breakage ligation and an elevated frequency of sister chromatid exchange (SCE). However, the introduction of XRCC1 rectified the deficiency in the DNA repair capacity of this particular cell line.

Fig. 3
figure 3

List and domain structures of XRCC1–6

Human XRCC2 is located at 7q36.1 and contains three exons [27]. XRCC2 is a newly discovered member of the RecA/Rad51 family of recombinant repair proteins. It is highly conserved in mammals and humans and encompasses the characteristic ATP-binding region typical of the Rad51 family [28]. The functions of XRCC2 include recruitment of the core protein Rad51 to the broken end of DNA, enhancement of Rad51 activity, maintenance of chromosome stability, and repair of DNA damage [29]. The loss of XRCC2 expression can result in a defect in the core protein RAD51, leading to a significant reduction in the homologous recombination repair (HRR) function, particularly concerning DNA double-strand breaks. As a consequence, DNA damage cannot be effectively and timely repaired, giving rise to a considerably increased risk of chromosomal aberrations and abnormal chromosomal separation [30].

Human XRCC3 is located on chromosome 14 q32.3, and the protein it encodes is involved in the recombination repair process of DNA double-strand breaks. The function of XRCC3 was first identified in irs1SF cells, a Chinese hamster ovary (CHO) cell line. Transfection of the cloned XRCC3 cDNA into irs1SF cells significantly improved chromosomal instability and reduced the sensitivity of irs1SF cells to various mutagens [31]. Liu et al. sequenced XRCC3 and found homology with RAD51, a repair and recombination gene in eukaryotic cells; they further demonstrated the interaction between the two encoded proteins through a series of basic experiments. This indicates that the XRCC3 protein belongs to the RAD51-related protein family and plays a key role in the homologous recombination process, essential for preserving chromosome stability and repairing DNA damage [32].

Human XRCC4 is located on chromosome 5q11.2–13.3 and encodes a 336 amino acid protein (Fig. 3). It exhibits a spherical N-terminal head structural domain comprising seven peptide chains folded into a flared β-barrel, which is further connected to a long helix tail. The process of polymerisation involves the association of the two head regions and the initial segments of their helix tails [33]. XRCC4 is an important NHEJ regulatory protein that directly interacts with Ku70/Ku80 in the repair pathway by preventing the degradation of free damaged DNA ends [34, 35]. XRCC4 can form a complex with DNA ligase IV and XLF, and then form an elastic link between Ku70/Ku80 and DNA ligase IV, guiding the damaged DNA ends to join each other, so that DNA can be repaired [36, 37].

Human XRCC5 is located at 2q33–34 and encodes a 732-amino acid protein with a molecular mass of approximately 86 kDa [38] (Fig. 3). XRCC5, also known as Ku80, together with XRCC6 (Ku70) constitutes the XRCC5/XRCC6 heterodimer (Ku80/Ku70), which is a DNA-dependent protein kinase complex [37, 38]. The XRCC5/XRCC6 dimer binds to DNA double-stranded break ends and serves as an essential component of DNA nonhomologous end-joining repair [39].

Single nucleotide polymorphisms (SNPs) in the XRCC family and tumour susceptibility

Single nucleotide polymorphisms (SNPs) are alterations in DNA sequence that are caused by variations in a single base at the genomic level. As the most common form of genetic variation, SNPs are commonly found in the human genome and constitute more than 90% of all variations in human genomic DNA, with an average of one genotypic polymorphic SNP per thousand bases [40, 41]. SNPs may be found in both the coding and non-coding sequences of genes. SNPs located in the coding regions of genes, specifically those genes encoding immune response factors, have the potential to impact differences in gene expression or alter the structure of proteins they encode [42, 43]. Numerous studies have highlighted the potential function of SNPs, such as their impact on gene or protein modifications, promoter activity, and the modification of transcription factor binding sites. Moreover, SNPs can also influence the subcellular localisation of RNA and/or proteins. In addition, SNPs are associated with certain human traits and can influence an individual’s susceptibility to specific diseases. Therefore, conducting an in-depth study of disease-associated SNPs and disease-susceptibility genes, along with analysing their functions, can significantly improve disease prevention strategies [44,45,46,47]. SNPs in the XRCC family of proteins play a significant role in causing individual variations in DNA damage repair ability, which in turn determines an individual’s susceptibility to tumours. Consequently, it is imperative to investigate genetic polymorphisms and tumour susceptibility and to explore specific molecular markers for the early diagnosis and treatment of tumours (Table 2).

Table 2 The relationship between SNPs of XRCC1–6 and tumour

Extensive research on XRCC1 SNPs has unequivocally established their correlation with tumour risk, treatment response, and survival outcomes in diverse malignancies, including lung cancer and gastric cancer [48,49,50,51]. Several SNPs have been detected within the coding region of XRCC1 that result in corresponding amino acid changes in the encoding protein. The C→T base transition in exon 6 of XRCC1 results in the conversion of the amino acid encoded by codon 194 from Arg to Trp, leading to the formation of the XRCCl Arg194Trp gene polymorphism; the G→A base transition in exon 10 of XRCC1 results in the conversion of the amino acid encoded by codon 399 from Arg to Gln, resulting in the formation of Arg399Gln gene polymorphism. Furthermore, the G→A base transition in exon 9 at position 27,466 results in the formation of Arg280His gene polymorphism [52]. XRCC2 gene polymorphisms can potentially lead to alterations in the primary structure of XRCC2 or abnormal protein expression, resulting in impaired repair of DNA damage and increased susceptibility to cancer. Polymorphisms in XRCC2 are associated with the development of various cancers, including lung, gastric, cervical, colon, breast, and others. Gok et al. reported that the Arg188His locus polymorphism of XRCC2 was significantly associated with the development of gastric cancer. Furthermore, Perez et al. demonstrated that the rs3218536 locus polymorphism of XRCC2 was substantially associated with the risk of cervical cancer pathogenesis. In addition, Sirisena and Kluzniak reported that SNPs in XRCC2 are associated with the risk of breast cancer pathogenesis [53,54,55,56,57]. XRCC3 possesses multiple SNPs, and certain XRCC3 SNPs have been inextricably linked to tumorigenesis, cancer progression, and susceptibility to treatment. These SNPs have the potential to serve as molecular indicators for predicting tumorigenesis and prognosis [58]. Several studies have demonstrated that the Thr241Met SNP of XRCC3 is associated with susceptibility to various cancers, including lung, bladder, endometrial, and laryngeal cancers [59,60,61,62,63]. The SNP of XRCC4 G1394T has been reported to be associated with colorectal carcinogenesis and susceptibility to lung and prostate cancer [64]. Furthermore, the c.1394G>T SNP in XRCC4 is associated with the development of breast cancer in Filipinos [65]. This study suggests that SNPs of XRCC5 are associated with the development and progression of various tumours. Liu et al. observed that rs828704, rs3770502, and rs9288516 SNPs in XRCC5 are associated with an increased risk of glioma susceptibility [66]. Hayden et al. observed that individuals carrying the TT genotype exhibited a reduced risk of myeloma compared with those carrying the XRCC5 rs2440 CC genotype [67]. The structure and function of XRCC6 are regulated by multiple SNPs and are closely associated with the development and progression of several tumours. Numerous studies have reported that SNPs of XRCC6 are associated with genetic susceptibility to various cancers, including head and neck, bladder, lung, kidney, prostate, oral, and gastric cancers [68,69,70,71]. In addition, XRCC7 SNP at allele 3434Thr has been reported to be associated with the risk of thyroid cancer in Iranian patients [72].

Role of XRCC in tumour metastasis

Metastasis refers to the process by which malignant tumour cells spread and establish secondary growths at distant sites from the primary tumour. The dissemination occurs through various means, including the lymphatic vessels, blood vessels, or body cavities from the primary site. Metastasis of malignant tumours is a major cause of death in cancer patients and a crucial factor affecting patient prognosis [73]. The XRCC family has been reported to regulate tumour metastasis by employing a variety of mechanisms. For instance, XRCC1 is expressed at low levels in clear cell renal cell carcinoma (ccRCC) tissues in contrast to normal tissues. The ccRCC tissues with low XRCC1 expression exhibit a positive correlation with lymph node metastasis and are associated with an unfavourable prognosis. Mechanistically, XRCC1 inhibits tumour cell invasion and metastasis by regulating the expression of tissue inhibitors of matrix metalloproteinase-2 (TIMP-2) and TIMP-1, leading to the suppression of the expression of metastasis-related markers matrix metalloproteinase-2 (MMP-2) and MMP-9 [74]. Additionally, the inhibition of XRCC1 expression is associated with the progression of primary and metastatic melanoma [75]. The meta-analysis conducted by Bashir et al. revealed a significant downregulation of XRCC2 in breast cancer tissues as opposed to non-cancerous healthy tissues. They also observed a significant correlation between XRCC2 expression, lymph node status, and metastatic status in patients with breast cancer. These findings suggest that dysregulation of XRCC2 in breast cancer could be utilized as a predictive indicator for lymph node metastasis and may serve as a therapeutic role in patients with breast cancer who are at risk of metastasis [76]. In colorectal cancer, the Thr241Met polymorphism of XRCC3 is associated with time-to-metastasis and may potentially play a biological role in accelerating the metastatic process [77]. In breast cancer, scoring XRCC4 expression using immunohistochemistry has proven to be effective in predicting postoperative breast cancer metastasis. In addition, the combined diagnosis of XRCC4, PARP1, and excision repair cross-complementation group 1 (ERCC1) has demonstrated considerable predictive capability in assessing the risk of breast cancer metastasis [78]. XRCC5, a downstream gene of miRNA-188-5p, was reported to be upregulated in glioma samples. In contrast, miRNA-188-5p was down-regulated in these samples, and patients with glioma exhibiting low miRNA-188-5p expression levels showed higher rates of distant metastasis. In addition, it is observed that miRNA-188-5p regulates glioma cell metastasis by suppressing XRCC5 expression [79]. In hepatocellular carcinoma, there is a positive correlation between XRCC5 expression level and the migration and invasion abilities of hepatocellular carcinoma cells. Inhibition of XRCC5 expression leads to a significant reduction in the migration and invasion abilities of hepatocellular carcinoma cells. Additionally, high XRCC5 expression is associated with tumour size, microvascular invasion, and lower overall survival time in the clinical samples of patients with hepatocellular carcinoma. Mechanistically, XRCC5 regulates the expression of CTNNB1 (beta-catenin 1) and MMP9, which are key downstream target molecules of the Wnt/β-catenin signalling pathway. Through this regulatory function, XRCC5 promotes the progression of hepatocellular carcinoma [80]. Luo et al. reported that testicular expression 10 (TEX10) may potentially regulate cancer cell proliferation and metastatic processes through XRCC6, thereby controlling the Wnt/β-catenin signalling pathway and DNA repair channels [81]. These data suggest that the XRCC gene family plays an crucial role in tumour metastasis via multiple mechanisms.

Role of XRCC in tumour immunity

At present, tumour immunotherapy is the most promising strategy for cancer treatment. It is used to treat tumours by harnessing the body’s immune system, enabling it to actively combat tumours, eradicate tumour cells, and establish sustained immune memory. Unlike targeted therapy, which focuses on specific targets, immunotherapy eliminates tumour cells by activating the body’s immune system and utilising immunoactive substances and immune cells produced by the body [82, 83]. Several immune checkpoints associated with tumour immunity have been identified, including cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1), programmed death ligand 1 (PD-L1), T-cell immunoglobulin and mucin-domain containing protein-3 (TIM3), and lymphocyte activating 3 (LAG3), among others [84,85,86,87]. Damaged DNA repair and associated genomic instability not only elevate mutagenicity and oncogenicity but also augment the neoantigenic load on the surface of tumour cells, thereby increasing their immunogenicity [88, 89]. The XRCC family is closely associated with tumour immunity.

In colorectal cancer samples, mutations of XRCC1 were significantly correlated with adenomas. Aberrant XRCC1 expression and mutations contribute to adenoma carcinogenesis. Moreover, PD-1/PD-L1 expression and CD4+ intraepithelial lymphocytes (IELs) are associated with tumour progression in patients possessing the wild-type XRCC1, suggesting that XRCC1 expression is correlated with patient survival, tumour-infiltrating lymphocytes, and immune marker expression [90]. Using bioinformatics analysis, Li et al. observed that in breast cancer XRCC2 and XRCC3 are associated with the infiltration of immune cells, such as B cells, CD4+ T cells, CD8/CD4+ T cells, neutrophils, and dendritic cells, as well as the prognosis of patients with breast cancer [91]. In head and neck, lung and cervical cancers, the methylation status of XRCC3 is associated with the expression of immune checkpoint molecules and inflammatory markers [92]. Guo et al. reported that retinoic acid-inducible gene I (RIG-I) can potentially be recruited to double-strand breaks (DSB) and inhibit NHEJ. Mechanistically, RIG-I hinders the formation of the XRCC4/LIG4/XLF complex on DSB by interacting with XRCC4, thereby disrupting DNA repair and rendering cancer cells sensitive to radiation therapy. XRCC4 enhances RIG-I oligomerization and ubiquitination to promote RIG-I signalling, thereby inhibiting RNA viral replication in host cells, indicating the crucial role played by XRCC4 in the innate immune response [19]. The cGAS-STING pathway has emerged as a potential mechanism for the induction of inflammation-mediated tumorigenesis [93, 94]. Qi et al. reported that XRCC5 and XRCC6 are associated with the cGAS-STING pathway. Overexpression of XRCC5 and XRCC6 was significantly associated with the clinical stage and pathological grade of hepatocellular carcinoma. Moreover, they observed a significant correlation between the expression of XRCC5 and XRCC6 and the infiltration of B cells, CD4+ T cells, CD8+ T cells, macrophages, neutrophils, and dendritic cells in hepatocellular carcinoma [95]. In addition, the toll-like receptor 4 (TLR4)-mediated lack of immune activity inhibits the expression of XRCC5 and XRCC6 in response to damage by the carcinogen diethylnitrosamine (DEN). This effect leads to the impairment of DNA repair, facilitating the transformation of precancerous hepatocytes and the progression of HCC. In contrast, XRCC6 expression prevents the development and progression of HCC by restoring the cellular senescence response and activating the immune network, thereby inducing efficient autophagic degradation, scavenging accumulated reactive oxygen species (ROS), reducing DNA damage, and attenuating proliferation [17, 96].

Role of XRCC in tumour metabolism

The abnormal metabolism of tumour cells is an important feature of tumours. As normal cells gradually develop into tumour cells, they acquire several hallmark capabilities. Abnormal alterations in energy metabolism are one of the primary hallmarks of malignancy [97]. Tumour cells perform several biosynthetic processes and metabolic activities in a metabolic reprogramming manner, providing energy and multiple substrates to support their rapid proliferation and survival [98]. The activation of oncogenes or inactivation of tumour suppressors drives the metabolic reprogramming of cancer cells, and the XRCC family plays a critical role in the tumour metabolic process.

In a recent study, Anurag et al. observed that proteomic analysis of pretreatment patient biopsies uniquely revealed metabolic pathways associated with drug resistance, including oxidative phosphorylation, lipogenesis, and fatty acid metabolism. Interestingly, proteogenomic analysis of somatic copy number aberrations identified a resistance-associated deletion in 19q13.31–33, which corresponded with the location of XRCC1 [99]. Aldehyde dehydrogenase 2 (ALDH2) is also involved in lipid metabolism. Chen et al. found that the interaction between the base excision repair proteins, XRCC1 and ALDH2, was indicative of overall survival in patients diagnosed with lung and liver cancer [100]. Folic acid metabolism is associated with the efficacy of platinum compounds [101, 102]. Folate metabolism involves DNA methylation mediated by the enzymes, tetrahydrofolate methylene reductase (MTHFR) and methionine synthase (MTR). Polymorphisms in XRCC1 and folate metabolism genes can affect the prognosis of patients with non-small cell lung cancer [103]. In addition, polymorphisms in DNA repair genes (including XRCC1, XRCC2, and XRCC3) and steroid metabolism genes in patients undergoing prostate cancer radiotherapy are associated with clinically advanced toxicity [104].

Role of XRCC in autophagy

Autophagy is a process by which self-damaged organelles and proteins are separated into autophagic vesicles and transported to lysosomes for catabolism [105]. Autophagy is closely associated with various diseases and plays a complex role in tumours. Particularly, autophagy plays an oncogenic role in early-stage tumours. Additionally, stressors such as nutritional deficiency, DNA damage, and cytotoxic effects can potentially induce cellular autophagy and promote malignant tumour progression in advanced-stage tumours or during antitumour therapy. Recent studies have shown that autophagy plays a dual regulatory role in promoting and inhibiting tumour cell growth; thus, targeting autophagy may significantly affect the efficacy of antitumour therapy [105].

Ma et al. conducted a comprehensive analysis including a cohort of 47 patients with advanced or metastatic oesophageal cancer who underwent next-generation sequencing (NGS) between May 2017 and February 2020. This study resulted in the identification of 227 mutated genes. Among them, XRCC1 exhibited a substantial number of mutations and was associated with autophagy [106]. Demirbag-Sarikaya et al. observed that the autophagy-related molecule autophagy-related protein 5 (ATG5) interacts with both XRCC5 and XRCC6. This interaction is primarily mediated by XRCC6. They also found the interaction to be dynamic and enhanced under genotoxic stress. Moreover, they found that the interaction between ATG5 and XRCC6 is essential for DNA repair and effective recovery from genotoxic stress. These results demonstrate a novel, direct, dynamic, and functional interaction between ATG5 and XRCC6, which are proteins that play critical roles in DNA repair under genotoxic stress conditions [107]. In addition, Wang et al. showed that the restoration of immunity supporting hepatocyte senescence and autophagy through XRCC6 repair of DNA damage reverses the progression of TLR4-deficient deteriorating hepatocellular carcinoma [17, 96].

The influence of non-coding RNAs on XRCC

Non-coding RNA (ncRNA) is an emerging biomarker that exhibits correlations with tumorigenesis and possesses oncogenic or tumour-suppressing properties. It can be detected in serum, plasma, and other biological fluids, making it a promising therapeutic and prognostic target for tumours, due to its non-invasive nature traumatic, high sensitivity, and specificity [108,109,110]. The ncRNAs, including long ncRNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), are extensively involved in tumour pathogenesis. The ncRNAs play a pivotal role in the biological processes of tumours by regulating cell growth and survival, EMT and metastasis, maintenance of tumour stem cells, metabolism, autophagy, chemoresistance, and angiogenesis [111, 112]. Several studies have reported that ncRNAs modulate tumour progression by regulating XRCC. In lung cancer, the circular RNA FLNA acts as a sponge for miR-486-3p and promotes tumour cell proliferation, migration, and invasion by regulating XRCC1 expression [113]. Li et al. observed that miR-3940-5p enhances homologous recombination repair after DSB by down-regulating XRCC2 expression [114]. In oesophageal cancer, microRNA-127-3p enhances the chemosensitivity of phenanthroline-dione derivatives by targeting XRCC3 [115]. In glioma cells, the long non-coding RNA SBF2-AS1 acts as a ceRNA for miR-151a-3p, which in turn regulates the expression of XRCC4, thereby enhancing DSB repair [116]. Furthermore, in hepatocellular carcinoma cells, lncRNA NIHCOLE promotes the ligation efficiency of DSB by regulating XRCC4 [117]. CircXRCC5 acts as a sponge for miR-490-3p and regulates the expression of the downstream target gene, XRCC5, thereby activating CLC3 transcription and promoting glioma progression [118]. In breast cancer, miR-623 inhibits cell proliferation, migration and invasion by targeting XRCC5 by downregulating cell cycle protein-dependent kinases and inhibiting phosphatidylinositol-3 kinase (PI3K)/Akt and Wnt/β-Catenin pathways [119]. The correlation between microRNA-379-5p and premature ovarian insufficiency has been reported to be mediated by PARP1 and XRCC6 [120].

Role of XRCC in tumour therapeutic sensitivity

Platinum-based combination chemotherapy represents the first-line standard of care for numerous types of tumours. The primary mechanism of action of platinum-based drugs is the formation of platinum–DNA adducts binding to guanine, adenine, and cytosine on DNA. This process leads to the creation of inter-strand or intra-strand DNA cross-links, ultimately causing DNA damage and cell death [121]. Differences in DNA repair ability directly lead to inter-individual differences in the sensitivity of tumour cells to DNA-related cytotoxic drugs [122]. Therefore, the relationship between DNA repair genes and tumour susceptibility to platinum-based chemotherapy may be crucial for guiding individualised clinical treatments. Similarly, the biological mechanism of killing tumour cells by radiation therapy is primarily based on direct genomic damage caused by radiation, resulting in the loss of the proliferative ability of tumour cells. Therefore, the clinical effect of radiation therapy depends on the responsiveness of tumour cells to radiation damage and their ability to repair the damage. However, tumour cells are highly capable of damage repair and can selectively recognise damage and initiate repair pathways, leading to tumour cell tolerance to radiation therapy and other antitumour drugs. Studies have demonstrated that DNA damage repair mechanisms protect tumour cells from radiation therapy-induced cell death, indicating that repair pathway proteins may play a potential role in enhancing tumour cell radiosensitivity. Exploring new approaches to more effectively inhibit repair proteins is crucial for enhancing tumour radiosensitivity [123].

DNA repair ability is associated with the Gln399Arg polymorphism in XRCC1. Patients with non-small cell lung cancer polymorphism may potentially be resistant to platinum [50, 124]. In a study involving 195 patients with epithelial ovarian cancer, it was observed that 45% of patients with XRCC1-positive tumours were resistant to platinum drugs. In contrast, only 17% of patients with XRCC1-negative tumours were resistant to platinum drugs. These findings suggest that XRCC1 has clinical significance as a predictor of resistance to platinum therapy in patients with ovarian cancer [125]. Xu et al. reported that the methylation level of H3K4 is significantly reduced in drug-resistant cells. JIB-04, a chemical inhibitor of H3K4 demethylase, restores the methylation of H3K4, blocks the co-localisation of XRCC1 and phosphorylation of H2AX (γH2AX), and ultimately improves drug sensitivity. They also found that the expression level of KDM5B was significantly elevated in drug-resistant cells. Knockdown of KDM5B elevates the methylation level of H3K4, which hinders the localisation of XRCC1 at the DNA damage site, resulting in heightened sensitivity [126]. Furthermore, in the context of gastric cancer, it has been reported that XRCC1 expression was significantly elevated in cisplatin-resistant cells, and it independently promoted cisplatin resistance. Irinotecan, another chemotherapeutic agent that induces DNA damage, was used to treat patients with advanced gastric cancer who experienced progression on cisplatin therapy. Notably, irinotecan effectively inhibited XRCC1 expression, resulting in increased sensitivity of resistant cells to cisplatin [127].

XRCC2 is indispensable for DNA repair following radiation damage. Radiation induces an abnormal increase in the expression level of XRCC2 in lung cancer cells, which causes them to resist the damaging effects of radiation on tumour cell DNA. This results in the development of tumour resistance to radiotherapy [128, 129]. In glioblastoma, inhibition of XRCC2 expression increases the radiosensitivity of tumour cells to radiation [130]. X-ray irradiation induces XRCC2 expression in colorectal cancer cells and exhibits a dose- and time-dependent relationship between XRCC2 expression and radiation exposure. Downregulation of XRCC2 expression inhibits the proliferation of colorectal cancer cells and increases their sensitivity to radiation. In addition, gene silencing of XRCC2 induces a decrease in the repair of radiation-induced cell damage, resulting in cellular arrest in the G2/M phase and increased apoptosis [131]. Expression abnormalities in XRCC3 are associated with tumour resistance to DNA damage-inducing antitumour agents. XRCC3 induces cisplatin resistance in tumour cells by activating Rad51-related recombination repair and S-phase monitor activation and by reducing apoptosis [132, 133]. XRCC3 has been reported to protect glioma cells from temozolomide (TMZ)-induced cell death and cell cycle inhibition. In addition, XRCC3 knockdown significantly reduces DSB repair after TMZ treatment, leading to increased drug sensitivity. This study confirms the importance of homologous recombination in conferring resistance to the methylating drug TMZ of glioma cells [18]. High XRCC3 expression is positively associated with resistance to radiotherapy in oesophagal squamous cell carcinoma (ESCC) and is an independent predictor of short disease-specific survival in patients with ESCC. Knockdown of XRCC3 in ESCC cells significantly improved the efficacy of radiotherapy in both in vitro and in vivo analyses. XRCC3 overexpression significantly enhanced the resistance of ESCC cells to radiotherapy. Furthermore, the radiation resistance of XRCC3 was mainly dependent on enhanced homologous recombination, telomere stabilisation, and ESCC cell death reduction mediated by radiation-induced apoptosis and mitotic mutations [134]. Overexpression of ubiquitin-like with PHD and RING finger domains 1 (UHRF1) increases XRCC4 expression Conversely, the downregulation of XRCC4 renders retinoblastoma cells sensitive to etoposide treatment, indicating that XRCC4 is a key mediator of drug sensitivity following UHRF1 consumption in retinoblastoma cells. Moreover, in retinoblastoma cells depleted of UHRF1, it was observed that the chromatin association of DNA ligase IV in response to acute DNA damage was significantly reduced. Functional complementation of XRCC4 in cells depleted of UHRF1 weakens drug sensitivity, indicating that the downregulation of XRCC4 in UHRF1-depleted cells impairs DNA repair, leading to a significant induction of apoptosis during treatment with genotoxic drugs [135]. Hori et al. investigated the relationship between NHEJ-related protein expression and the outcome of radiotherapy in oesophageal cancer. They employed immunohistochemical analysis of NHEJ-related proteins, including XRCC4, which holds promise as a potential predictive marker for assessing tumour radiosensitivity [136]. XRCC5 knockdown significantly enhanced the sensitivity of glioma cells to TMZ, whereas XRCC5 overexpression led to TMZ resistance in cancer cells. Both in vitro and in vivo experiments have shown that TMZ treatment induces XRCC5 expression in TMZ-resistant cells [137]. Chen et al. reported that the quercetin-targeted radiation-induced ARv7-mediated circNHS/miR-512-5p/XRCC5 signalling pathway increases radiosensitivity in prostate cancer [138].

Conclusions

Tumour development is the result of a complex interplay of various factors, and DNA damage is a significant contributor to this process. The XRCC gene family is a crucial group of genes involved in DNA damage repair responsible for maintaining the stability of genetic material and cellular function through their role in repairing DNA double-strand breaks and cross-link damage. Additionally, these genes play a significant role in ensuring the proper segregation of chromosomes during cell division. The XRCC family constitutes a group of susceptibility genes, and their polymorphisms are prevalent in the general population, exerting a substantial effect on tumorigenesis. An in-depth investigation of the correlation between XRCC gene polymorphisms and tumour development can help explore the interactions between related genes, as well as the interactions between genes and the environment. These investigations will substantially help in effectively formulating tumour prevention and treatment strategies, protecting the susceptible population to a larger extent, effectively reducing the incidence of tumours, and improving the cure rate of tumours. Although significant progress has been made, inconsistencies persist in the findings of several studies. Therefore, it is essential to increase the sample size and conduct a comprehensive population cohort study employing multivariate analysis of crucial prognostic factors, such as gender, age, smoking status, histopathological types, clinical stages, and treatment strategies. This approach enables the investigation of the correlation between gene polymorphisms and prognosis, as well as the interplay between genetic polymorphisms and environmental factors.

The mechanism of resistance to tumour radiotherapy and chemotherapy has been a popular research topic in the field of oncology. DNA oxygenation and alkylation damage caused by numerous DNA-damaging anticancer drugs can be repaired via the XRCC gene family-mediated pathways. Research on the XRCC gene family and chemotherapeutic drug sensitivity is of particular interest. Inhibition of the XRCC gene family expression can sensitise various anticancer drugs, suggesting the XRCC gene family has the potential to influence the efficacy of tumor therapy by affecting chemotherapy sensitisation. However, the functions of these genes are not fully understood, and their relationship with anticancer drug sensitisation requires further exploration.

Availability of data and materials

Not applicable.

Abbreviations

XRCC:

X-ray repair cross-complementary

IR:

Ionizing radiation

UV:

Ultraviolet

DDR:

DNA damage repair

BER:

Base excision repair

HR:

Homologous recombination

MMR:

Mismatch repair

NER:

Nucleotide excision repair

NHEJ:

Non-homologous end joining

DSB:

DNA double-strand breaks

EMS:

Ethyl methanesulfonate

SCE:

Sister chromatid exchange

PARP:

Poly(ADP-ribose) polymerase

SNP:

Single nucleotide polymorphisms

ccRCC:

Clear cell renal cell carcinoma

CTLA-4:

Cytotoxic T-lymphocyte antigen 4

PD-1:

Programmed death 1

PD-L1:

Programmed death ligand 1

IELs:

Intraepithelial lymphocytes

TLR4:

Toll-like receptor 4

DEN:

Diethylnitrosamine

ROS:

Reactive oxygen species

ALDH2:

Aldehyde dehydrogenase 2

MTR:

Methionine synthase

NGS:

Next-generation sequencing

ESCC:

Esophageal squamous cell carcinoma

TMZ:

Temozolomide

References

  1. Huang RX, Zhou PK. DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer. Signal Transduct Target Ther. 2020;5:60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Jackson SP, Bartek J. The DNA-damage response in human biology and disease. Nature. 2009;461:1071–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Silas Y, Singer E, Das K, Lehming N, Pines O. A combination of Class-I fumarases and metabolites (alpha-ketoglutarate and fumarate) signal the DNA damage response in Escherichia coli. Proc Natl Acad Sci USA. 2021;118:e2026595118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Lemay JF, St-Hilaire E, Ronato DA, Gao Y, Belanger F, Gezzar-Dandashi S, Kimenyi Ishimwe AB, Sawchyn C, Levesque D, McQuaid M, et al. A genome-wide screen identifies SCAI as a modulator of the UV-induced replicative stress response. PLoS Biol. 2022;20: e3001543.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Khozooei S, Lettau K, Barletta F, Jost T, Rebholz S, Veerappan S, Franz-Wachtel M, Macek B, Iliakis G, Distel LV, et al. Fisetin induces DNA double-strand break and interferes with the repair of radiation-induced damage to radiosensitize triple negative breast cancer cells. J Exp Clin Cancer Res. 2022;41:256.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Tarish FL, Schultz N, Tanoglidi A, Hamberg H, Letocha H, Karaszi K, Hamdy FC, Granfors T, Helleday T. Castration radiosensitizes prostate cancer tissue by impairing DNA double-strand break repair. Sci Transl Med. 2015;7:312re311.

    Article  Google Scholar 

  7. Sunada S, Nakanishi A, Miki Y. Crosstalk of DNA double-strand break repair pathways in poly(ADP-ribose) polymerase inhibitor treatment of breast cancer susceptibility gene 1/2-mutated cancer. Cancer Sci. 2018;109:893–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Maksoud S. The DNA double-strand break repair in glioma: molecular players and therapeutic strategies. Mol Neurobiol. 2022;59:5326–65.

    Article  CAS  PubMed  Google Scholar 

  9. Karakashev S, Fukumoto T, Zhao B, Lin J, Wu S, Fatkhutdinov N, Park PH, Semenova G, Jean S, Cadungog MG, et al. EZH2 inhibition sensitizes CARM1-high, homologous recombination proficient ovarian cancers to PARP inhibition. Cancer Cell. 2020;37(157–167): e156.

    Google Scholar 

  10. Hughes CD, Simons M, Mackenzie CE, Van Houten B, Kad NM. Single molecule techniques in DNA repair: a primer. DNA Repair (Amst). 2014;20:2–13.

    Article  CAS  PubMed  Google Scholar 

  11. Ciccia A, Elledge SJ. The DNA damage response: making it safe to play with knives. Mol Cell. 2010;40:179–204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Chapman JR, Taylor MR, Boulton SJ. Playing the end game: DNA double-strand break repair pathway choice. Mol Cell. 2012;47:497–510.

    Article  CAS  PubMed  Google Scholar 

  13. Chang HHY, Pannunzio NR, Adachi N, Lieber MR. Non-homologous DNA end joining and alternative pathways to double-strand break repair. Nat Rev Mol Cell Biol. 2017;18:495–506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Parry EM, Gable DL, Stanley SE, Khalil SE, Antonescu V, Florea L, Armanios M. Germline mutations in DNA repair genes in lung adenocarcinoma. J Thorac Oncol. 2017;12:1673–8.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Helleday T, Petermann E, Lundin C, Hodgson B, Sharma RA. DNA repair pathways as targets for cancer therapy. Nat Rev Cancer. 2008;8:193–204.

    Article  CAS  PubMed  Google Scholar 

  16. Zhao Z, He K, Zhang Y, Hua X, Feng M, Zhao Z, Sun Y, Jiang Y, Xia Q. XRCC2 repairs mitochondrial DNA damage and fuels malignant behavior in hepatocellular carcinoma. Cancer Lett. 2021;512:1–14.

    Article  CAS  PubMed  Google Scholar 

  17. Wang Z, Lin H, Hua F, Hu ZW. Repairing DNA damage by XRCC6/KU70 reverses TLR4-deficiency-worsened HCC development via restoring senescence and autophagic flux. Autophagy. 2013;9:925–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Roos WP, Frohnapfel L, Quiros S, Ringel F, Kaina B. XRCC3 contributes to temozolomide resistance of glioblastoma cells by promoting DNA double-strand break repair. Cancer Lett. 2018;424:119–26.

    Article  CAS  PubMed  Google Scholar 

  19. Guo G, Gao M, Gao X, Zhu B, Huang J, Tu X, Kim W, Zhao F, Zhou Q, Zhu S, et al. Reciprocal regulation of RIG-I and XRCC4 connects DNA repair with RIG-I immune signaling. Nat Commun. 2021;12:2187.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Gu Z, Li Y, Yang X, Yu M, Chen Z, Zhao C, Chen L, Wang L. Overexpression of CLC-3 is regulated by XRCC5 and is a poor prognostic biomarker for gastric cancer. J Hematol Oncol. 2018;11:115.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Alblihy A, Ali R, Algethami M, Shoqafi A, Toss MS, Brownlie J, Tatum NJ, Hickson I, Moran PO, Grabowska A, et al. Targeting Mre11 overcomes platinum resistance and induces synthetic lethality in XRCC1 deficient epithelial ovarian cancers. NPJ Precis Oncol. 2022;6:51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Fan Y, Gao Z, Li X, Wei S, Yuan K. Gene expression and prognosis of x-ray repair cross-complementing family members in non-small cell lung cancer. Bioengineered. 2021;12:6210–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Caldecott KW. XRCC1 and DNA strand break repair. DNA Repair (Amst). 2003;2:955–69.

    Article  CAS  PubMed  Google Scholar 

  24. Li D, Liu H, Jiao L, Chang DZ, Beinart G, Wolff RA, Evans DB, Hassan MM, Abbruzzese JL. Significant effect of homologous recombination DNA repair gene polymorphisms on pancreatic cancer survival. Cancer Res. 2006;66:3323–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Siciliano MJ, Carrano AV, Thompson LH. Assignment of a human DNA-repair gene associated with sister-chromatid exchange to chromosome 19. Mutat Res. 1986;174:303–8.

    Article  CAS  PubMed  Google Scholar 

  26. Thompson LH, Brookman KW, Jones NJ, Allen SA, Carrano AV. Molecular cloning of the human XRCC1 gene, which corrects defective DNA strand break repair and sister chromatid exchange. Mol Cell Biol. 1990;10:6160–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Romanowicz H, Smolarz B, Baszczynski J, Zadrozny M, Kulig A. Genetics polymorphism in DNA repair genes by base excision repair pathway (XRCC1) and homologous recombination (XRCC2 and RAD51) and the risk of breast carcinoma in the Polish population. Pol J Pathol. 2010;61:206–12.

    CAS  PubMed  Google Scholar 

  28. O’Regan P, Wilson C, Townsend S, Thacker J. XRCC2 is a nuclear RAD51-like protein required for damage-dependent RAD51 focus formation without the need for ATP binding. J Biol Chem. 2001;276:22148–53.

    Article  CAS  PubMed  Google Scholar 

  29. Tambini CE, Spink KG, Ross CJ, Hill MA, Thacker J. The importance of XRCC2 in RAD51-related DNA damage repair. DNA Repair (Amst). 2010;9:517–25.

    Article  CAS  PubMed  Google Scholar 

  30. Park SW, Yoo NJ, Lee SH. Mutational analysis of mononucleotide repeats in XRCC2 and XRCC6 in cancers with microsatellite instability. Pathology. 2011;43:78–9.

    Article  PubMed  Google Scholar 

  31. Fuller LF, Painter RB. A Chinese hamster ovary cell line hypersensitive to ionizing radiation and deficient in repair replication. Mutat Res. 1988;193:109–21.

    CAS  PubMed  Google Scholar 

  32. Tebbs RS, Zhao Y, Tucker JD, Scheerer JB, Siciliano MJ, Hwang M, Liu N, Legerski RJ, Thompson LH. Correction of chromosomal instability and sensitivity to diverse mutagens by a cloned cDNA of the XRCC3 DNA repair gene. Proc Natl Acad Sci USA. 1995;92:6354–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Junop MS, Modesti M, Guarne A, Ghirlando R, Gellert M, Yang W. Crystal structure of the Xrcc4 DNA repair protein and implications for end joining. EMBO J. 2000;19:5962–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Wu PY, Frit P, Meesala S, Dauvillier S, Modesti M, Andres SN, Huang Y, Sekiguchi J, Calsou P, Salles B, Junop MS. Structural and functional interaction between the human DNA repair proteins DNA ligase IV and XRCC4. Mol Cell Biol. 2009;29:3163–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Pastwa E, Blasiak J. Non-homologous DNA end joining. Acta Biochim Pol. 2003;50:891–908.

    Article  CAS  PubMed  Google Scholar 

  36. Ramsden DA, Gellert M. Ku protein stimulates DNA end joining by mammalian DNA ligases: a direct role for Ku in repair of DNA double-strand breaks. EMBO J. 1998;17:609–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Gottlieb TM, Jackson SP. The DNA-dependent protein kinase: requirement for DNA ends and association with Ku antigen. Cell. 1993;72:131–42.

    Article  CAS  PubMed  Google Scholar 

  38. Rathmell WK, Chu G. Involvement of the Ku autoantigen in the cellular response to DNA double-strand breaks. Proc Natl Acad Sci USA. 1994;91:7623–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lees-Miller SP, Godbout R, Chan DW, Weinfeld M, Day RS 3rd, Barron GM, Allalunis-Turner J. Absence of p350 subunit of DNA-activated protein kinase from a radiosensitive human cell line. Science. 1995;267:1183–5.

    Article  CAS  PubMed  Google Scholar 

  40. Li Y, Zhang F, Yang D. Comprehensive assessment and meta-analysis of the association between CTNNB1 polymorphisms and cancer risk. Biosci Rep. 2017. https://doi.org/10.1042/BSR20171121.

    Article  PubMed  PubMed Central  Google Scholar 

  41. International HapMap Consortium, Frazer KA, Ballinger DG, Cox DR, Hinds DA, Stuve LL, Gibbs RA, Belmont JW, Boudreau A, Hardenbol P, et al. A second generation human haplotype map of over 3.1 million SNPs. Nature. 2007;449:851–61.

    Article  Google Scholar 

  42. Dickinson AM, Norden J. Non-HLA genomics: does it have a role in predicting haematopoietic stem cell transplantation outcome? Int J Immunogenet. 2015;42:229–38.

    Article  CAS  PubMed  Google Scholar 

  43. Bogunia-Kubik K, Lacina P. From genetic single candidate gene studies to complex genomics of GvHD. Br J Haematol. 2017;178:661–75.

    Article  CAS  PubMed  Google Scholar 

  44. Yige L, Dandan Z. Progress on functional mechanisms of colorectal cancer causal SNPs in post-GWAS. Yi Chuan. 2021;43:203–14.

    PubMed  Google Scholar 

  45. Pittman AM, Naranjo S, Jalava SE, Twiss P, Ma Y, Olver B, Lloyd A, Vijayakrishnan J, Qureshi M, Broderick P, et al. Allelic variation at the 8q23.3 colorectal cancer risk locus functions as a cis-acting regulator of EIF3H. PLoS Genet. 2010;6: e1001126.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Dayeh TA, Olsson AH, Volkov P, Almgren P, Ronn T, Ling C. Identification of CpG-SNPs associated with type 2 diabetes and differential DNA methylation in human pancreatic islets. Diabetologia. 2013;56:1036–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Civelek M, Lusis AJ. Systems genetics approaches to understand complex traits. Nat Rev Genet. 2014;15:34–48.

    Article  CAS  PubMed  Google Scholar 

  48. Ruzzo A, Graziano F, Kawakami K, Watanabe G, Santini D, Catalano V, Bisonni R, Canestrari E, Ficarelli R, Menichetti ET, et al. Pharmacogenetic profiling and clinical outcome of patients with advanced gastric cancer treated with palliative chemotherapy. J Clin Oncol. 2006;24:1883–91.

    Article  CAS  PubMed  Google Scholar 

  49. Liu B, Wei J, Zou Z, Qian X, Nakamura T, Zhang W, Ding Y, Feng J, Yu L. Polymorphism of XRCC1 predicts overall survival of gastric cancer patients receiving oxaliplatin-based chemotherapy in Chinese population. Eur J Hum Genet. 2007;15:1049–53.

    Article  CAS  PubMed  Google Scholar 

  50. Gurubhagavatula S, Liu G, Park S, Zhou W, Su L, Wain JC, Lynch TJ, Neuberg DS, Christiani DC. XPD and XRCC1 genetic polymorphisms are prognostic factors in advanced non-small-cell lung cancer patients treated with platinum chemotherapy. J Clin Oncol. 2004;22:2594–601.

    Article  CAS  PubMed  Google Scholar 

  51. Chen B, Zhou Y, Yang P, Wu XT. Polymorphisms of XRCC1 and gastric cancer susceptibility: a meta-analysis. Mol Biol Rep. 2012;39:1305–13.

    Article  CAS  PubMed  Google Scholar 

  52. Yin J, Vogel U, Ma Y, Qi R, Sun Z, Wang H. The DNA repair gene XRCC1 and genetic susceptibility of lung cancer in a northeastern Chinese population. Lung Cancer. 2007;56:153–60.

    Article  PubMed  Google Scholar 

  53. Wojcik KA, Synowiec E, Polakowski P, Blasiak J, Szaflik J, Szaflik JP. Variation in DNA base excision repair genes in fuchs endothelial corneal dystrophy. Med Sci Monit. 2015;21:2809–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Sirisena ND, Samaranayake N, Dissanayake VHW. Electrophoretic mobility shift assays implicate XRCC2:rs3218550C>T as a potential low-penetrant susceptibility allele for sporadic breast cancer. BMC Res Notes. 2019;12:476.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Kluzniak W, Wokolorczyk D, Rusak B, Huzarski T, Gronwald J, Stempa K, Rudnicka H, Kashyap A, Debniak T, Jakubowska A, et al. Inherited variants in XRCC2 and the risk of breast cancer. Breast Cancer Res Treat. 2019;178:657–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Gok I, Baday M, Cetinkunar S, Kilic K, Bilgin BC. Polymorphisms in DNA repair genes XRCC2 and XRCC3 risk of gastric cancer in Turkey. Bosn J Basic Med Sci. 2014;14:214–8.

    PubMed  PubMed Central  Google Scholar 

  57. Balkan E, Bilici M, Gundogdu B, Aksungur N, Kara A, Yasar E, Dogan H, Ozturk G. ERCC2 Lys751Gln rs13181 and XRCC2 Arg188His rs3218536 gene polymorphisms contribute to subsceptibility of colon, gastric, HCC, lung and prostate cancer. J BUON. 2020;25:574–81.

    PubMed  Google Scholar 

  58. Daboussi F, Dumay A, Delacote F, Lopez BS. DNA double-strand break repair signalling: the case of RAD51 post-translational regulation. Cell Signal. 2002;14:969–75.

    Article  CAS  PubMed  Google Scholar 

  59. Sun H, Qiao Y, Zhang X, Xu L, Jia X, Sun D, Shen C, Liu A, Zhao Y, Jin Y, et al. XRCC3 Thr241Met polymorphism with lung cancer and bladder cancer: a meta-analysis. Cancer Sci. 2010;101:1777–82.

    Article  CAS  PubMed  Google Scholar 

  60. Santos EM, Santos HBP, de Matos FR, Machado RA, Coletta RD, Galvao HC, Freitas RA. Clinicopathological significance of SNPs in RAD51 and XRCC3 in oral and oropharyngeal carcinomas. Oral Dis. 2019;25:54–63.

    Article  PubMed  Google Scholar 

  61. Samara M, Papathanassiou M, Mitrakas L, Koukoulis G, Vlachostergios PJ, Tzortzis V. DNA repair gene polymorphisms and susceptibility to urothelial carcinoma in a southeastern European population. Curr Oncol. 2021;28:1879–85.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Rajagopal T, Seshachalam A, Rathnam KK, Talluri S, Venkatabalasubramanian S, Dunna NR. Homologous recombination DNA repair gene RAD51, XRCC2 & XRCC3 polymorphisms and breast cancer risk in South Indian women. PLoS ONE. 2022;17: e0259761.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Mutlu P, Mutlu M, Yalcin S, Yaylaci A, Unsoy G, Saylam G, Akin I, Gunduz U, Korkmaz H. Association between XRCC3 Thr241Met polymorphism and laryngeal cancer susceptibility in Turkish population. Eur Arch Otorhinolaryngol. 2015;272:3779–84.

    Article  PubMed  Google Scholar 

  64. Jin D, Zhang M, Hua H. Impact of polymorphisms in DNA repair genes XPD, hOGG1 and XRCC4 on colorectal cancer risk in a Chinese Han population. Biosci Rep. 2019. https://doi.org/10.1042/BSR20181074.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Garcia JA, Kalacas NA, Sy Ortin T, Ramos MC, Albano PM. XRCC4 c.1394G>T single nucleotide polymorphisms and breast cancer risk among Filipinos. Asian Pac J Cancer Prev. 2019;20:1097–101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Liu Y, Zhang H, Zhou K, Chen L, Xu Z, Zhong Y, Liu H, Li R, Shugart YY, Wei Q, et al. Tagging SNPs in non-homologous end-joining pathway genes and risk of glioma. Carcinogenesis. 2007;28:1906–13.

    Article  CAS  PubMed  Google Scholar 

  67. Hayden PJ, Tewari P, Morris DW, Staines A, Crowley D, Nieters A, Becker N, de Sanjose S, Foretova L, Maynadie M, et al. Variation in DNA repair genes XRCC3, XRCC4, XRCC5 and susceptibility to myeloma. Hum Mol Genet. 2007;16:3117–27.

    Article  CAS  PubMed  Google Scholar 

  68. Corral R, Lewinger JP, Van Den Berg D, Joshi AD, Yuan JM, Gago-Dominguez M, Cortessis VK, Pike MC, Conti DV, Thomas DC, et al. Comprehensive analyses of DNA repair pathways, smoking and bladder cancer risk in Los Angeles and Shanghai. Int J Cancer. 2014;135:335–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Christmann M, Tomicic MT, Roos WP, Kaina B. Mechanisms of human DNA repair: an update. Toxicology. 2003;193:3–34.

    Article  CAS  PubMed  Google Scholar 

  70. Blankenburg S, Konig IR, Moessner R, Laspe P, Thoms KM, Krueger U, Khan SG, Westphal G, Berking C, Volkenandt M, et al. Assessment of 3 xeroderma pigmentosum group C gene polymorphisms and risk of cutaneous melanoma: a case-control study. Carcinogenesis. 2005;26:1085–90.

    Article  CAS  PubMed  Google Scholar 

  71. Aref S, El Menshawy N, Abou Zeid T, Gouda E, Abdel Aziz N. DNA repair genes polymorphisms: impact on acute myeloid leukemia patients outcome. Asian Pac J Cancer Prev. 2022;23:3577–85.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Jamshidi M, Farnoosh G, Mohammadi Pour S, Rafiee F, Saeedi Boroujeni A, Mahmoudian-Sani MR. Genetic variants and risk of thyroid cancer among Iranian patients. Horm Mol Biol Clin Investig. 2021;42:223–34.

    Article  CAS  PubMed  Google Scholar 

  73. Suhail Y, Cain MP, Vanaja K, Kurywchak PA, Levchenko A, Kalluri R. Kshitiz: systems biology of cancer metastasis. Cell Syst. 2019;9:109–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Liu QH, Wang Y, Yong HM, Hou PF, Pan J, Bai J, Zheng JN. XRCC1 serves as a potential prognostic indicator for clear cell renal cell carcinoma and inhibits its invasion and metastasis through suppressing MMP-2 and MMP-9. Oncotarget. 2017;8:109382–92.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Bhandaru M, Martinka M, Li G, Rotte A. Loss of XRCC1 confers a metastatic phenotype to melanoma cells and is associated with poor survival in patients with melanoma. Pigment Cell Melanoma Res. 2014;27:366–75.

    Article  CAS  PubMed  Google Scholar 

  76. Bashir N, Sana S, Mahjabeen I, Kayani MA. Association of reduced XRCC2 expression with lymph node metastasis in breast cancer tissues. Fam Cancer. 2014;13:611–7.

    Article  CAS  PubMed  Google Scholar 

  77. He Y, Penney ME, Negandhi AA, Parfrey PS, Savas S, Yilmaz YE. XRCC3 Thr241Met and TYMS variable number tandem repeat polymorphisms are associated with time-to-metastasis in colorectal cancer. PLoS ONE. 2018;13: e0192316.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Yang Y, Li X, Hao L, Jiang D, Wu B, He T, Tang Y. The diagnostic value of DNA repair gene in breast cancer metastasis. Sci Rep. 2020;10:19626.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Leng N, Zhou W, Jiang L, Zhao Y, Zhou M, Sun S, Nie W. Biological functions of miRNA-188-5p/XRCC5 in the metastasis of glioma. J BUON. 2021;26:359–65.

    PubMed  Google Scholar 

  80. Liu ZH, Wang N, Wang FQ, Dong Q, Ding J. High expression of XRCC5 is associated with metastasis through Wnt signaling pathway and predicts poor prognosis in patients with hepatocellular carcinoma. Eur Rev Med Pharmacol Sci. 2019;23:7835–47.

    PubMed  Google Scholar 

  81. Luo S, Wang W, Feng J, Li R. TEX10 promotes the tumorigenesis and radiotherapy resistance of urinary bladder carcinoma by stabilizing XRCC6. J Immunol Res. 2021;2021:5975893.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Zhang Y, Zhang Z. The history and advances in cancer immunotherapy: understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications. Cell Mol Immunol. 2020;17:807–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Pulendran B, Davis MM. The science and medicine of human immunology. Science. 2020. https://doi.org/10.1126/science.aay4014.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Palacios LM, Peyret V, Viano ME, Geysels RC, Chocobar YA, Volpini X, Pellizas CG, Nicola JP, Motran CC, Rodriguez-Galan MC, Fozzatti L. TIM3 expression in anaplastic-thyroid-cancer-infiltrating macrophages: an emerging immunotherapeutic target. Biology. 2022;11:1609.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Mittal N, Singh S, Mittal R, Kaushal J, Kaushal V. Immune checkpoint inhibitors as neoadjuvant therapy in early triple-negative breast cancer: a systematic review and meta-analysis. J Cancer Res Ther. 2022;18:1754–65.

    Article  CAS  PubMed  Google Scholar 

  86. Michelson DA, Benoist C, Mathis D. CTLA-4 on thymic epithelial cells complements Aire for T cell central tolerance. Proc Natl Acad Sci USA. 2022;119: e2215474119.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Maruhashi T, Sugiura D, Okazaki IM, Okazaki T. LAG-3: from molecular functions to clinical applications. J Immunother Cancer. 2020. https://doi.org/10.1136/jitc-2020-001014.

  88. Jiang M, Jia K, Wang L, Li W, Chen B, Liu Y, Wang H, Zhao S, He Y, Zhou C. Alterations of DNA damage response pathway: biomarker and therapeutic strategy for cancer immunotherapy. Acta Pharm Sin B. 2021;11:2983–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Green AR, Aleskandarany MA, Ali R, Hodgson EG, Atabani S, De Souza K, Rakha EA, Ellis IO, Madhusudan S. Clinical impact of tumor DNA repair expression and T-cell infiltration in breast cancers. Cancer Immunol Res. 2017;5:292–9.

    Article  CAS  PubMed  Google Scholar 

  90. Zhang Y, Zhang X, Jin Z, Chen H, Zhang C, Wang W, Jing J, Pan W. Clinical impact of X-ray repair cross-complementary 1 (XRCC1) and the immune environment in colorectal adenoma-carcinoma pathway progression. J Inflamm Res. 2021;14:5403–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Li F, Zhang Y, Shi Y, Liu S. Comprehensive analysis of prognostic and immune infiltrates for RAD51 in human breast cancer. Crit Rev Eukaryot Gene Expr. 2021;31:71–9.

    Article  PubMed  Google Scholar 

  92. Rieke DT, Ochsenreither S, Klinghammer K, Seiwert TY, Klauschen F, Tinhofer I, Keilholz U. Methylation of RAD51B, XRCC3 and other homologous recombination genes is associated with expression of immune checkpoints and an inflammatory signature in squamous cell carcinoma of the head and neck, lung and cervix. Oncotarget. 2016;7:75379–93.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Barbie DA, Tamayo P, Boehm JS, Kim SY, Moody SE, Dunn IF, Schinzel AC, Sandy P, Meylan E, Scholl C, et al. Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature. 2009;462:108–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Ahn J, Xia T, Konno H, Konno K, Ruiz P, Barber GN. Inflammation-driven carcinogenesis is mediated through STING. Nat Commun. 2014;5:5166.

    Article  CAS  PubMed  Google Scholar 

  95. Qi Z, Yan F, Chen D, Xing W, Li Q, Zeng W, Bi B, Xie J. Identification of prognostic biomarkers and correlations with immune infiltrates among cGAS-STING in hepatocellular carcinoma. Biosci Rep. 2020. https://doi.org/10.1042/BSR20202603.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Wang Z, Yan J, Lin H, Hua F, Wang X, Liu H, Lv X, Yu J, Mi S, Wang J, Hu ZW. Toll-like receptor 4 activity protects against hepatocellular tumorigenesis and progression by regulating expression of DNA repair protein Ku70 in mice. Hepatology. 2013;57:1869–81.

    Article  CAS  PubMed  Google Scholar 

  97. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

    Article  CAS  PubMed  Google Scholar 

  98. Pavlova NN, Thompson CB. The emerging hallmarks of cancer metabolism. Cell Metab. 2016;23:27–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Anurag M, Jaehnig EJ, Krug K, Lei JT, Bergstrom EJ, Kim BJ, Vashist TD, Huynh AMT, Dou Y, Gou X, et al. Proteogenomic markers of chemotherapy resistance and response in triple-negative breast cancer. Cancer Discov. 2022;12:2586–605.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Chen X, Legrand AJ, Cunniffe S, Hume S, Poletto M, Vaz B, Ramadan K, Yao D, Dianov GL. Interplay between base excision repair protein XRCC1 and ALDH2 predicts overall survival in lung and liver cancer patients. Cell Oncol. 2018;41:527–39.

    Article  CAS  Google Scholar 

  101. Matakidou A, El Galta R, Rudd MF, Webb EL, Bridle H, Eisen T, Houlston RS. Prognostic significance of folate metabolism polymorphisms for lung cancer. Br J Cancer. 2007;97:247–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Adjei AA, Salavaggione OE, Mandrekar SJ, Dy GK, Ziegler KL, Endo C, Molina JR, Schild SE, Adjei AA. Correlation between polymorphisms of the reduced folate carrier gene (SLC19A1) and survival after pemetrexed-based therapy in non-small cell lung cancer: a North Central cancer treatment group-based exploratory study. J Thorac Oncol. 2010;5:1346–53.

    Article  PubMed  PubMed Central  Google Scholar 

  103. Perez-Ramirez C, Canadas-Garre M, Alnatsha A, Villar E, Valdivia-Bautista J, Faus-Dader MJ, Calleja-Hernandez MA. Pharmacogenetics of platinum-based chemotherapy: impact of DNA repair and folate metabolism gene polymorphisms on prognosis of non-small cell lung cancer patients. Pharmacogenom J. 2019;19:164–77.

    Article  CAS  Google Scholar 

  104. Damaraju S, Murray D, Dufour J, Carandang D, Myrehaug S, Fallone G, Field C, Greiner R, Hanson J, Cass CE, Parliament M. Association of DNA repair and steroid metabolism gene polymorphisms with clinical late toxicity in patients treated with conformal radiotherapy for prostate cancer. Clin Cancer Res. 2006;12:2545–54.

    Article  CAS  PubMed  Google Scholar 

  105. Kimmelman AC, White E. Autophagy and tumor metabolism. Cell Metab. 2017;25:1037–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Ma Y, Li W, Chen S, Lin S, Ding S, Zhou X, Liu T, Wang R, Wang W. Characteristics and response to next-generation sequencing-guided therapy in locally advanced or metastatic esophageal cancer. Int J Cancer. 2022;152(3):436–46.

    Article  PubMed  Google Scholar 

  107. Demirbag-Sarikaya S, Akkoc Y, Turgut S, Erbil-Bilir S, Kocaturk NM, Dengjel J, Gozuacik D. A novel ATG5 interaction with Ku70 potentiates DNA repair upon genotoxic stress. Sci Rep. 2022;12:8134.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Shirvani H, Ghanavi J, Aliabadi A, Mousavinasab F, Talebi M, Majidpoor J, Najafi S, Miryounesi SM, Aghaei Zarch SM. MiR-211 plays a dual role in cancer development: from tumor suppressor to tumor enhancer. Cell Signal. 2023;101: 110504.

    Article  CAS  PubMed  Google Scholar 

  109. Faramin Lashkarian M, Hashemipour N, Niaraki N, Soghala S, Moradi A, Sarhangi S, Hatami M, Aghaei-Zarch F, Khosravifar M, Mohammadzadeh A, et al. MicroRNA-122 in human cancers: from mechanistic to clinical perspectives. Cancer Cell Int. 2023;23:29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Bahari Khasraghi L, Nouri M, Vazirzadeh M, Hashemipour N, Talebi M, Aghaei Zarch F, Majidpoor J, Kalhor K, Farnia P, Najafi S, Aghaei Zarch SM. MicroRNA-206 in human cancer: mechanistic and clinical perspectives. Cell Signal. 2023;101: 110525.

    Article  CAS  PubMed  Google Scholar 

  111. Goodall GJ, Wickramasinghe VO. RNA in cancer. Nat Rev Cancer. 2021;21:22–36.

    Article  CAS  PubMed  Google Scholar 

  112. Anastasiadou E, Jacob LS, Slack FJ. Non-coding RNA networks in cancer. Nat Rev Cancer. 2018;18:5–18.

    Article  CAS  PubMed  Google Scholar 

  113. Pan J, Huang G, Yin Z, Cai X, Gong E, Li Y, Xu C, Ye Z, Cao Z, Cheng W. Circular RNA FLNA acts as a sponge of miR-486-3p in promoting lung cancer progression via regulating XRCC1 and CYP1A1. Cancer Gene Ther. 2022;29:101–21.

    Article  CAS  PubMed  Google Scholar 

  114. Li Y, Hu G, Li P, Tang S, Zhang J, Jia G. miR-3940-5p enhances homologous recombination after DSB in Cr(VI) exposed 16HBE cell. Toxicology. 2016;344–346:1–6.

    Article  PubMed  Google Scholar 

  115. Zhen N, Yang Q, Zheng K, Han Z, Sun F, Mei W, Yu Y. MiroRNA-127-3p targets XRCC3 to enhance the chemosensitivity of esophageal cancer cells to a novel phenanthroline-dione derivative. Int J Biochem Cell Biol. 2016;79:158–67.

    Article  CAS  PubMed  Google Scholar 

  116. Zhang Z, Yin J, Lu C, Wei Y, Zeng A, You Y. Exosomal transfer of long non-coding RNA SBF2-AS1 enhances chemoresistance to temozolomide in glioblastoma. J Exp Clin Cancer Res. 2019;38:166.

    Article  PubMed  PubMed Central  Google Scholar 

  117. Unfried JP, Marin-Baquero M, Rivera-Calzada A, Razquin N, Martin-Cuevas EM, de Braganca S, Aicart-Ramos C, McCoy C, Prats-Mari L, Arribas-Bosacoma R, et al. Long noncoding RNA NIHCOLE promotes ligation efficiency of DNA double-strand breaks in hepatocellular carcinoma. Cancer Res. 2021;81:4910–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Chen P, Nie ZY, Liu XF, Zhou M, Liu XX, Wang B. CircXRCC5, as a potential novel biomarker, promotes glioma progression via the miR-490-3p/XRCC5/CLC3 competing endogenous RNA network. Neuroscience. 2022;494:104–18.

    Article  CAS  PubMed  Google Scholar 

  119. Li Q, Liu J, Jia Y, Li T, Zhang M. miR-623 suppresses cell proliferation, migration and invasion through direct inhibition of XRCC5 in breast cancer. Aging. 2020;12:10246–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Dang Y, Wang X, Hao Y, Zhang X, Zhao S, Ma J, Qin Y, Chen ZJ. MicroRNA-379-5p is associate with biochemical premature ovarian insufficiency through PARP1 and XRCC6. Cell Death Dis. 2018;9:106.

    Article  PubMed  PubMed Central  Google Scholar 

  121. Hildebrandt MA, Gu J, Wu X. Pharmacogenomics of platinum-based chemotherapy in NSCLC. Expert Opin Drug Metab Toxicol. 2009;5:745–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Kiyohara C, Takayama K, Nakanishi Y. Association of genetic polymorphisms in the base excision repair pathway with lung cancer risk: a meta-analysis. Lung Cancer. 2006;54:267–83.

    Article  PubMed  Google Scholar 

  123. Jorgensen TJ. Enhancing radiosensitivity: targeting the DNA repair pathways. Cancer Biol Ther. 2009;8:665–70.

    Article  CAS  PubMed  Google Scholar 

  124. Rosell R, Taron M, Barnadas A, Scagliotti G, Sarries C, Roig B. Nucleotide excision repair pathways involved in Cisplatin resistance in non-small-cell lung cancer. Cancer Control. 2003;10:297–305.

    Article  PubMed  Google Scholar 

  125. Abdel-Fatah T, Sultana R, Abbotts R, Hawkes C, Seedhouse C, Chan S, Madhusudan S. Clinicopathological and functional significance of XRCC1 expression in ovarian cancer. Int J Cancer. 2013;132:2778–86.

    Article  CAS  PubMed  Google Scholar 

  126. Xu W, Zhou B, Zhao X, Zhu L, Xu J, Jiang Z, Chen D, Wei Q, Han M, Feng L, et al. KDM5B demethylates H3K4 to recruit XRCC1 and promote chemoresistance. Int J Biol Sci. 2018;14:1122–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Xu W, Wang S, Chen Q, Zhang Y, Ni P, Wu X, Zhang J, Qiang F, Li A, Roe OD, et al. TXNL1-XRCC1 pathway regulates cisplatin-induced cell death and contributes to resistance in human gastric cancer. Cell Death Dis. 2014;5: e1055.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Shan J, Wang X, Zhao J. XRCC2 reduced the sensitivity of NSCLC to radio-chemotherapy by arresting the cell cycle. Am J Transl Res. 2022;14:3783–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  129. He Y, Xue B, Xiong X, Wu W, Li X, Zhao H. Correlation analysis between XRCC2 polymorphism and radiosensitivity of non-small cell lung cancer. Panminerva Med. 2021. https://doi.org/10.23736/S0031-0808.21.04472-4.

    Article  PubMed  Google Scholar 

  130. Zheng Z, Ng WL, Zhang X, Olson JJ, Hao C, Curran WJ, Wang Y. RNAi-mediated targeting of noncoding and coding sequences in DNA repair gene messages efficiently radiosensitizes human tumor cells. Cancer Res. 2012;72:1221–8.

    Article  CAS  PubMed  Google Scholar 

  131. Wang Q, Wang Y, Du L, Xu C, Sun Y, Yang B, Sun Z, Fu Y, Cai L, Fan S, et al. shRNA-mediated XRCC2 gene knockdown efficiently sensitizes colon tumor cells to X-ray irradiation in vitro and in vivo. Int J Mol Sci. 2014;15:2157–71.

    Article  PubMed  PubMed Central  Google Scholar 

  132. Xu ZY, Loignon M, Han FY, Panasci L, Aloyz R. Xrcc3 induces cisplatin resistance by stimulation of Rad51-related recombinational repair, S-phase checkpoint activation, and reduced apoptosis. J Pharmacol Exp Ther. 2005;314:495–505.

    Article  CAS  PubMed  Google Scholar 

  133. Xu Z, Chen ZP, Malapetsa A, Alaoui-Jamali M, Bergeron J, Monks A, Myers TG, Mohr G, Sausville EA, Scudiero DA, et al. DNA repair protein levels vis-a-vis anticancer drug resistance in the human tumor cell lines of the National Cancer Institute drug screening program. Anticancer Drugs. 2002;13:511–9.

    Article  CAS  PubMed  Google Scholar 

  134. Cheng J, Liu W, Zeng X, Zhang B, Guo Y, Qiu M, Jiang C, Wang H, Wu Z, Meng M, et al. XRCC3 is a promising target to improve the radiotherapy effect of esophageal squamous cell carcinoma. Cancer Sci. 2015;106:1678–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. He H, Lee C, Kim JK. UHRF1 depletion sensitizes retinoblastoma cells to chemotherapeutic drugs via downregulation of XRCC4. Cell Death Dis. 2018;9:164.

    Article  PubMed  PubMed Central  Google Scholar 

  136. Hori M, Someya M, Matsumoto Y, Nakata K, Kitagawa M, Hasegawa T, Tsuchiya T, Fukushima Y, Gocho T, Sato Y, et al. Influence of XRCC4 expression in esophageal cancer cells on the response to radiotherapy. Med Mol Morphol. 2017;50:25–33.

    Article  CAS  PubMed  Google Scholar 

  137. Lee IN, Yang JT, Huang C, Huang HC, Wu YP, Chen JC. Elevated XRCC5 expression level can promote temozolomide resistance and predict poor prognosis in glioblastoma. Oncol Lett. 2021;21:443.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Chen D, Chou FJ, Chen Y, Huang CP, Tian H, Wang Y, Niu Y, You B, Yeh S, Xing N, Chang C. Targeting the radiation-induced ARv7-mediated circNHS/miR-512-5p/XRCC5 signaling with Quercetin increases prostate cancer radiosensitivity. J Exp Clin Cancer Res. 2022;41:235.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Mei PJ, Bai J, Miao FA, Li ZL, Chen C, Zheng JN, Fan YC. Relationship between expression of XRCC1 and tumor proliferation, migration, invasion, and angiogenesis in glioma. Invest New Drugs. 2019;37:646–57.

    Article  CAS  PubMed  Google Scholar 

  140. Zheng Y, Zhang H, Guo Y, Chen Y, Chen H, Liu Y. X-ray repair cross-complementing protein 1 (XRCC1) loss promotes beta-lapachone -induced apoptosis in pancreatic cancer cells. BMC Cancer. 2021;21:1234.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Xu K, Song X, Chen Z, Qin C, He Y, Zhan W. XRCC2 promotes colorectal cancer cell growth, regulates cell cycle progression, and apoptosis. Medicine. 2014;93: e294.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Yan CT, Kaushal D, Murphy M, Zhang Y, Datta A, Chen C, Monroe B, Mostoslavsky G, Coakley K, Gao Y, et al. XRCC4 suppresses medulloblastomas with recurrent translocations in p53-deficient mice. Proc Natl Acad Sci USA. 2006;103:7378–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Zhang Z, Zheng F, Yu Z, Hao J, Chen M, Yu W, Guo W, Chen Y, Huang W, Duan Z, Deng W. XRCC5 cooperates with p300 to promote cyclooxygenase-2 expression and tumor growth in colon cancers. PLoS ONE. 2017;12: e0186900.

    Article  PubMed  PubMed Central  Google Scholar 

  144. Kim JH, Park SY, Jeon SE, Choi JH, Lee CJ, Jang TY, Yun HJ, Lee Y, Kim P, Cho SH, et al. DCLK1 promotes colorectal cancer stemness and aggressiveness via the XRCC5/COX2 axis. Theranostics. 2022;12:5258–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Zhu B, Cheng D, Li S, Zhou S, Yang Q. High expression of XRCC6 promotes human osteosarcoma cell proliferation through the beta-Catenin/Wnt signaling pathway and is associated with poor prognosis. Int J Mol Sci. 2016;17:1188.

    Article  PubMed  PubMed Central  Google Scholar 

  146. Tang B, Zhang Y, Wang W, Qi G, Shimamoto F. PARP6 suppresses the proliferation and metastasis of hepatocellular carcinoma by degrading XRCC6 to regulate the Wnt/beta-catenin pathway. Am J Cancer Res. 2020;10:2100–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Naguib M, Helwa MM, Soliman MM, Abdel-Samiee M, Eljaky AM, Hammam O, Zaghla H, Abdelsameea E. XRCC1 gene polymorphism increases the risk of hepatocellular carcinoma in Egyptian population. Asian Pac J Cancer Prev. 2020;21:1031–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Sobiahe A, Hijazi E, Al-Ameer HJ, Almasri Y, Jarrar Y, Zihlif M, Shomaf M, Al-Rawashdeh B. Arg399Gln XRCC1 polymorphism and risk of squamous cell carcinoma of the head and neck in Jordanian patients. Asian Pac J Cancer Prev. 2020;21:663–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Wang F, Zhao Q, He HR, Zhai YJ, Lu J, Hu HB, Zhou JS, Yang YH, Li YJ. The association between XRCC1 Arg399Gln polymorphism and risk of leukemia in different populations: a meta-analysis of case-control studies. Onco Targets Ther. 2015;8:3277–87.

    PubMed  PubMed Central  Google Scholar 

  150. Zhang L, Zhao J, Yu B, Song X, Sun G, Han L, Wang L, Dong S. Correlations between microsatellite instability, ERCC1/XRCC1 polymorphism and clinical characteristics, and FOLFOX adjuvant chemotherapy effect of colorectal cancer patients. Cancer Genet. 2017;218–219:51–7.

    Article  PubMed  Google Scholar 

  151. Lin WY, Camp NJ, Cannon-Albright LA, Allen-Brady K, Balasubramanian S, Reed MW, Hopper JL, Apicella C, Giles GG, Southey MC, et al. A role for XRCC2 gene polymorphisms in breast cancer risk and survival. J Med Genet. 2011;48:477–84.

    Article  CAS  PubMed  Google Scholar 

  152. Michalska MM, Samulak D, Bienkiewicz J, Romanowicz H, Smolarz B. Association between -41657C/T single nucleotide polymorphism of DNA repair gene XRCC2 and endometrial cancer risk in Polish women. Pol J Pathol. 2015;66:67–71.

    Article  PubMed  Google Scholar 

  153. Pasqualetti F, Gonnelli A, Orlandi P, Palladino E, Giannini N, Gadducci G, Mattioni R, Montrone S, Calistri E, Mazzanti CM, et al. Association of XRCC3 rs1799794 polymorphism with survival of glioblastoma multiforme patients treated with combined radio-chemotherapy. Invest New Drugs. 2021;39:1159–65.

    Article  CAS  PubMed  Google Scholar 

  154. Nowacka-Zawisza M, Raszkiewicz A, Kwasiborski T, Forma E, Brys M, Rozanski W, Krajewska WM. RAD51 and XRCC3 polymorphisms are associated with increased risk of prostate cancer. J Oncol. 2019;2019:2976373.

    Article  PubMed  PubMed Central  Google Scholar 

  155. Gresner P, Gromadzinska J, Polanska K, Twardowska E, Jurewicz J, Wasowicz W. Genetic variability of Xrcc3 and Rad51 modulates the risk of head and neck cancer. Gene. 2012;504:166–74.

    Article  CAS  PubMed  Google Scholar 

  156. Singh PK, Mistry KN, Chiramana H, Rank DN, Joshi CG. Exploring the deleterious SNPs in XRCC4 gene using computational approach and studying their association with breast cancer in the population of West India. Gene. 2018;655:13–9.

    Article  CAS  PubMed  Google Scholar 

  157. Makkoch J, Praianantathavorn K, Sopipong W, Chuaypen N, Tangkijvanich P, Payungporn S. Genetic variations in XRCC4 (rs1805377) and ATF6 (rs2070150) are not associated with hepatocellular carcinoma in Thai patients with hepatitis B virus infection. Asian Pac J Cancer Prev. 2016;17:591–5.

    Article  PubMed  Google Scholar 

  158. Hasan SK, Buttari F, Ottone T, Voso MT, Hohaus S, Marasco E, Mantovani V, Garagnani P, Sanz MA, Cicconi L, et al. Risk of acute promyelocytic leukemia in multiple sclerosis: coding variants of DNA repair genes. Neurology. 2011;76:1059–65.

    Article  CAS  PubMed  Google Scholar 

  159. Willems P, De Ruyck K, Van den Broecke R, Makar A, Perletti G, Thierens H, Vral A. A polymorphism in the promoter region of Ku70/XRCC6, associated with breast cancer risk and oestrogen exposure. J Cancer Res Clin Oncol. 2009;135:1159–68.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

This work was supported in part by grants from the following sources: the National Natural Science Foundation of China (82203233), the Natural Science Foundation of Hunan Province (2022JJ70101, 2023JJ40413), the Research Project of Health Commission of Hunan Province (202302067467).

Author information

Authors and Affiliations

Authors

Contributions

QL, QP, BZ and YT collected the related paper and drafted the manuscript. BZ and YT revised and finalized the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Bin Zhang or Yueqiu Tan.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, Q., Peng, Q., Zhang, B. et al. X-ray cross-complementing family: the bridge linking DNA damage repair and cancer. J Transl Med 21, 602 (2023). https://doi.org/10.1186/s12967-023-04447-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12967-023-04447-2

Keywords