Widespread BRCA1/2-independent homologous recombination defects are caused by alterations in RNA-binding proteins.

ABSTRACT: Defects in homologous recombination DNA repair (HRD) both predispose to cancer development and produce therapeutic vulnerabilities, making it critical to define the spectrum of genetic events that cause HRD. However, we found that mutations in BRCA1/2 and other canonical HR genes only identified 10%-20% of tumors that display genomic evidence of HRD. Using a networks-based approach, we discovered that over half of putative genes causing HRD originated outside of canonical DNA damage response genes, with a particular enrichment for RNA-binding protein (RBP)-encoding genes. These putative drivers of HRD were experimentally validated, cross-validated in an independent cohort, and enriched in cancer-associated genome-wide association study loci. Mechanistic studies indicate that some RBPs are

SUBMITTER: McGrail DJ 

PROVIDER: S-EPMC10694618 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature