CpG dinucleotides are hotspots for mutagenesis by spontaneous deamination of 5-methylcytosine (5mC) into thymine, resulting in T:G mismatches that can lead to C>T transitions. These mutations are not only a hallmark of aging and cancer but also a major force shaping the evolution of vertebrate genomes. We have previously uncovered MBD4 as the primary base excision repair (BER) glycosylase responsible for 5mC deamination repair in both CpG and non-CpG contexts, with a striking preference for guarding active chromatin and early-replicating DNA. In this study, we employ a targeted base-editing system—comprising an APOBEC1 deaminase fused to a catalytically dead Cas9—to induce precise and strand-specific cytosine deamination and track its repair. This approach allows us to systematically investigate the cellular components required for efficient 5mC deamination repair in human cells. Our data reveal that MBD4 cooperates with the mismatch repair (MMR) pathway outside of S-phase, implicating non-canonical MMR in the repair of this form of DNA damage. Using AI-based structural predictions alongside biochemical validation, we identify a previously unrecognized complex including MBD4 and MMR components, positioning them as key players in a coordinated repair response. Finally, we analyze thousands of tumor whole-genomes to show that MMR deficiency leads to CpG hypermutagenesis lacking replication strand asymmetry, further supporting a role for replication-independent MMR activity in 5mC deamination repair. Altogether, we uncover a novel function of non-canonical MMR that underscores its interplay with BER in safeguarding genomic integrity in mammalian cells. Paris postdoc seminar series

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