Widespread BRCA1/2-Independent Homologous Recombination Defects Are Caused by Alterations in RNA-Binding Proteins

Authors

Daniel J McGrail
Yang Li
Roger S Smith
Bin Feng
Hui Dai
Limei Hu
Briana Dennehey
Sharad Awasthi
Marc L Mendillo
Anil K Sood
Gordon B Mills
Shiaw-Yih Lin
S Stephen Yi
Nidhi Sahni

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

Comments

Supplementary Materials

Data Availability Statement

PMID: 37909041