DNA replication initiation drives focal mutagenesis and rearrangements in human cancers
Murat, P.; Guilbaud, G.; Sale, J. E.
Show 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 regulators of tumour biology and demonstrate that replication initiation both passively and actively drives focal mutagenesis in cancer genomes.
Matching journals
The top 2 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Transcription start sites experience a high influx of heritable variants fuelled by early development 98%
- ANP32E drives vulnerability to ATR inhibitors by inducing R-loops-dependent Transcription Replication Conflicts in Triple Negative Breast Cancer 98%
- RNA Transcripts Serve as a Template for Double-Strand Break Repair in Human Cells 98%
Similar papers in this journal
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.