J Biochem 2025 Apr 02;1774:247-258. doi: 10.1093/jb/mvaf007.

Replication across O6-methylguanine activates futile cycling of DNA mismatch repair attempts assisted by the chromatin-remodelling enzyme Smarcad1.

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SN1-type alkylating reagents generate O6-methylguanine (meG) lesions that activate the mismatch repair (MMR) response. Since post-replicative MMR specifically targets the nascent strand, meG on the template strand is refractory to rectification by MMR and, therefore, can induce non-productive MMR reactions. The cycling of futile MMR attempts is proposed to cause DNA double-strand breaks in the subsequent S phase, leading to ATR-checkpoint-mediated G2 arrest and apoptosis. However, the mechanistic details of futile MMR cycling, especially how this reaction is maintained in chromatin, remain unclear. Using replication-competent Xenopus egg extracts, we herein establish an in vitro system that recapitulates futile MMR cycling in the chromatin context. The meG-T mispair, but not the meG-C pair, is efficiently targeted by MMR in our system. MMR attempts on the meG-strand result in the meG-to-A correction, whilst those on the T-strand induce iterative cycles of strand excision and resynthesis. Likewise, replication across meG generates persistent single-strand breaks on the daughter DNA containing meG. Moreover, the depletion of Smarcad1, a chromatin remodeller previously reported to facilitate MMR, impairs the retention of single-strand breaks. Our study thus provides experimental evidence that chromatin replication across meG induces futile MMR cycling that is assisted by Smarcad1.

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