Base-excision repair pathway shapes 5-methylcytosine deamination signatures in pan-cancer genomes

André Bortolini Silveira (), Alexandre Houy, Olivier Ganier, Begüm Özemek, Sandra Vanhuele, Anne Vincent-Salomon, Nathalie Cassoux, Pascale Mariani, Gaelle Pierron, Serge Leyvraz, Damian Rieke, Alberto Picca, Franck Bielle, Marie-Laure Yaspo, Manuel Rodrigues and Marc-Henri Stern ()
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André Bortolini Silveira: PSL Research University
Alexandre Houy: PSL Research University
Olivier Ganier: PSL Research University
Begüm Özemek: Max Planck Institute for Molecular Genetics
Sandra Vanhuele: PSL Research University
Anne Vincent-Salomon: Institut Curie, PSL Research University
Nathalie Cassoux: Paris Cité University
Pascale Mariani: Institut Curie, PSL Research University
Gaelle Pierron: PSL Research University
Serge Leyvraz: Charité - Universitätsmedizin Berlin
Damian Rieke: Charité - Universitätsmedizin Berlin
Alberto Picca: Hôpital de la Pitié-Salpêtrière
Franck Bielle: ICM
Marie-Laure Yaspo: Max Planck Institute for Molecular Genetics
Manuel Rodrigues: PSL Research University
Marc-Henri Stern: PSL Research University

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract 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. We integrate mutational signatures analysis in a large series of tumor whole genomes with lineage-specific epigenomic data to draw a detailed view of 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. Here, we establish MBD4 as the main actor responsible for 5mC deamination repair in humans.

Date: 2024
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DOI: 10.1038/s41467-024-54223-z

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