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

In an article published in Mucosal Immunology, scientists show that IgA antibodies present in mucous membranes play a key role against HIV. By triggering the destruction of infected cells, which then ...

We study the interactions between immune cells and their immediate environment in health and disease. In this context, we have focussed on mesenchymal, lymphatic endothelial and B cells. The mesenchym...

Influenza continues to be a significant health problem and the virus causes a wide disease span from mild to fatal. The elderly are an at-risk population for developing severe influenza disease, but i...

Persistent exposure to antigen during chronic infection or cancer renders T cells dysfunctional. The molecular mechanisms regulating this state of exhaustion are thought to be common in infection and ...

The prevailing view considers homologous recombination to be a tumour-suppressing mechanism. However, a re-analysis of data and concepts published in the journal Oncogene concludes that, in fact, homo...

The opportunistic human fungal pathogen Candida albicans displays a high degree of morphological plasticity, with the ability to switch between at least 7 different forms, depending on its environment...

Raphaël Scharfmann has been nominated for the Albert Renold Award (2025) from the European Association for the Study of Diabetes e.V. (EASD) The Albert Renold Award recognizes outstanding achievement ...