Student and Faculty Publications
Publication Date
11-21-2023
Journal
Cell Reports Medicine
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 recruited to sites of DNA damage to facilitate repair, whereas others control the expression of canonical HR genes. Overall, this study greatly expands the repertoire of known drivers of HRD, with implications for basic biology, genetic screening, and therapy stratification.
Keywords
homologous recombination, DNA damage, BRCA1, BRCA2, RNA binding proteins, breast cancer, hereditary cancer, network biology, PARP inhibitors
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Medical Sciences Commons, Oncology Commons
Comments
Supplementary Materials
Data Availability Statement
PMID: 37909041