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Base-excision repair pathway shapes 5-methylcytosine deamination signatures in pan-cancer genomes (CUT&RUN)

GSE275181 Homo sapiens Genome binding/occupancy profiling by high throughput sequencing 9 samples Submitted 2024/09/12 Platform GPL24676
Summary
Transition of cytosine to thymine in CpG dinucleotides is the most frequent type of mutation in cancer. This increased mutability is commonly attributed to the spontaneous deamination of 5-methylcytosine (5mC), which is normally repaired by the base-excision repair (BER) pathway. However, the contribution of 5mC deamination in the increasing diversity of cancer mutational signatures remains poorly explored. Here, we integrate mutational signatures analysis in a large series of tumor whole genomes with lineage-specific epigenomic data to draw a detailed view on 5mC deamination in cancer. We uncover tumor type-specific patterns of 5mC deamination signatures in CpG and non-CpG contexts. We demonstrate that the BER glycosylase MBD4 preferentially binds to active chromatin and early replicating DNA, which correlates with lower mutational burden in these domains. We validate our findings by modeling BER deficiencies in isogenic cell models. Overall, we establish MBD4 as the main actor responsible for 5mC deamination repair in humans.
Published in
Base-excision repair pathway shapes 5-methylcytosine deamination signatures in pan-cancer genomes
Silveira AB, Houy A, Ganier O et al. · Nature communications 2024 · PMID 39543136 · doi:10.1038/s41467-024-54223-z
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Also filed as BioProject PRJNA1149724 and SRA study SRP527319. Searching any of these in the dataset finder brings you back here.

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