Speaker: Sarah Aitken, PhD FRCPathGroup Leader | MRC Toxicology Unit, University of Cambridge, UK NIHR Clinical Lecturer | Cambridge University Hospitals NHS Foundation Trust, UK
Host: Núria López-Bigas
Node: Computational Biology / Preclinical Models of Cancer
Date: Wednesday 27 April 2022, 12.00h
Cancers arise through the acquisition of oncogenic mutations and grow by clonal expansion. Here we reveal that most mutagenic DNA lesions are not resolved into a mutated DNA base pair within a single cell cycle. Instead, DNA lesions segregate, unrepaired, into daughter cells for multiple cell generations, resulting in the chromosome-scale phasing of subsequent mutations. Furthermore, DNA replication across these persisting lesions can produce multiple alternative alleles in successive cell divisions, thereby generating both multiallelic and combinatorial genetic diversity. We exploit our discovery of lesion segregation to reveal how strand-asymmetric processes such as replication, transcription, and protein interactions shape DNA damage and repair. We demonstrate that replication over lesions produces almost identical collateral mutagenesis on the leading and lagging strands. In transcription, the triggering of repair is stochastic with frequent lesion bypass by RNA-polymerase. Finally, defining multiallelic variation patterns, we examine patterns of mutations in accessible chromatin regions as well as transcription factor binding sites. These results provide insight into how strand asymmetric mechanisms underlie the formation, tolerance, and repair of DNA damage and thus shape cancer genome evolution.