Fig. 8

Working model of cellular processing of aberrantly (MMS-) methylated mRNA. MMS-induced m¹A and m³C mediate direct ribosomal stalling, whereas m⁷G may form translation-blocking secondary structures. Collided disomes are detected by ZNF598, which serves two functions: It stabilizes GIGYF2-4EHP to block cap-dependent 43S entry and facilitates recruitment of ASCC3/ALKBH3 to mediate ribosome splitting and removal of m¹A/m³C. Repaired transcripts can then be re-routed directly to translation. Transcripts harboring persistent blocking lesions, e.g. MMS-induced secondary structures, are stripped of ribosomes by ASCC3 and accumulate in P-bodies. Here, helicase activities relieve secondary structures to promote repair by ALBH3, whereas nonrepairable mRNAs are degraded