DNA replication initiation drives focal mutagenesis and rearrangements in human cancers

Pierre Murat (), Guillaume Guilbaud and Julian E. Sale ()
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Pierre Murat: Francis Crick Avenue
Guillaume Guilbaud: Francis Crick Avenue
Julian E. Sale: Francis Crick Avenue

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract The rate and pattern of mutagenesis in cancer genomes is significantly influenced by DNA accessibility and active biological processes. Here we show that efficient sites of replication initiation drive and modulate specific mutational processes in cancer. Sites of replication initiation impede nucleotide excision repair in melanoma and are off-targets for activation-induced deaminase (AICDA) activity in lymphomas. Using ductal pancreatic adenocarcinoma as a cancer model, we demonstrate that the initiation of DNA synthesis is error-prone at G-quadruplex-forming sequences in tumours displaying markers of replication stress, resulting in a previously recognised but uncharacterised mutational signature. Finally, we demonstrate that replication origins serve as hotspots for genomic rearrangements, including structural and copy number variations. These findings reveal replication origins as functional determinants of tumour biology and demonstrate that replication initiation both passively and actively drives focal mutagenesis in cancer genomes.

Date: 2024
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DOI: 10.1038/s41467-024-55148-3

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