Widespread BRCA1/2-independent homologous recombination defects are caused by alterations in RNA-binding proteins
Year: 2023
Type: article
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.
Source: Cell Reports Medicine
Institutions: Cleveland Clinic, The University of Texas MD Anderson Cancer Center, Northwestern University, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, GlaxoSmithKline (United States), Oregon Health & Science University, OHSU Knight Cancer Institute, The University of Texas at Austin, Baylor College of Medicine
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,460
Funders: U.S. Department of Defense, American Cancer Society, U.S. Department of Veterans Affairs, Susan G. Komen for the Cure, Breast Cancer Alliance, AstraZeneca, Cancer Prevention and Research Institute of Texas, Susan G. Komen, Sidney Kimmel Foundation, Frank McGraw Memorial Chair in Cancer Research, Ovarian Cancer Research Fund Alliance, Ovarian Cancer Research Alliance, National Institutes of Health, University of Texas MD Anderson Cancer Center, National Cancer Institute, National Institute of General Medical Sciences
Awards: G1099926228, G111615301, G1468253849, G1901027039, CHARACTERIZING AND TARGETING REPLICATION STRESS RESPONSE DEFECTS IN BREAST CANCER, G2779272668, G3400176136, Elucidating the stress response regulatory networks that enable malignancy, G4095781974, G4119534169, G510513728, G5653070311, G5850682332, Integrative bioinformatics and functional characterization of oncogenic driver aberrations in cancer, Recruitment of First-Time, Tenure-Track Faculty Members, G6736661663, G7264742132, G788993117, G8227738726, G9000005305, G9000076341
OpenAlex ID: W4388098349