DNA replication initiation drives focal mutagenesis and rearrangements in human cancers.

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 rearrangemen

SUBMITTER: Murat P 

PROVIDER: S-EPMC11685606 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature