BRCA2 promotes genomic integrity and therapy resistance primarily through its role in homology-directed repair Journal Article

   

Authors:	Lim, P. X.; Zaman, M.; Feng, W.; Jasin, M.
Article Title:	BRCA2 promotes genomic integrity and therapy resistance primarily through its role in homology-directed repair
Abstract:	Tumor suppressor BRCA2 functions in homology-directed repair (HDR), the protection of stalled replication forks, and the suppression of replicative gaps, but their relative contributions to genome integrity and chemotherapy response are under scrutiny. Here, we report that mouse and human cells require a RAD51 filament stabilization motif in BRCA2 for fork protection and gap suppression but not HDR. In mice, the loss of fork protection/gap suppression does not compromise genome stability or shorten tumor latency. By contrast, HDR deficiency increases spontaneous and replication stress-induced chromosome aberrations and tumor predisposition. Unlike with HDR, fork protection/gap suppression defects are also observed in Brca2 heterozygous cells, likely due to reduced RAD51 stabilization at stalled forks/gaps. Gaps arise from PRIMPOL activity, which is associated with 5-hydroxymethyl-2′-deoxyuridine sensitivity due to the formation of SMUG1-generated abasic sites and is exacerbated by poly(ADP-ribose) polymerase (PARP) inhibition. However, HDR proficiency has the major role in mitigating sensitivity to chemotherapeutics, including PARP inhibitors. © 2023 Elsevier Inc.
Keywords:	genetics; dna replication; mouse; animal; metabolism; animals; mice; homologous recombination; dna repair; brca2 protein; genomic instability; genomics; brca2; rad51 protein; rad51 recombinase; homology-directed repair; rad51; brca2 protein, human; recombinational dna repair; recombination repair; humans; human; parp inhibitors; gap suppression; hmdu; primpol; stalled fork protection
Journal Title:	Molecular Cell
Volume:	84
Issue:	3
ISSN:	1097-2765
Publisher:	Cell Press
Date Published:	2024-02-01
Start Page:	447
End Page:	462.e10
Language:	English
DOI:	10.1016/j.molcel.2023.12.025
PUBMED:	38244544
PROVIDER:	scopus
PMCID:	PMC11188060
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85183525184&doi=10.1016%2fj.molcel.2023.12.025&partnerID=40&md5=bf6ccd82af2e681d7a81dcba09319253
Notes:	The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF. Corresponding MSK author is Maria Jasin -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/213922