Homology-Directed Repair and the Role of BRCA1, BRCA2, and Related Proteins in Genome Integrity and Cancer

Overview

Journal Annu Rev Cancer Biol

Publisher Annual Reviews

Date 2018 Oct 23

PMID 30345412

Citations 157

Authors

Chun-Chin Chen

Weiran Feng

Pei Xin Lim

Elizabeth M Kass

Maria Jasin

Affiliations

Soon will be listed here.

Abstract

Germ-line and somatic mutations in genes that promote homology-directed repair (HDR), especially and , are frequently observed in several cancers, in particular, breast and ovary but also prostate and other cancers. HDR is critical for the error-free repair of DNA double-strand breaks and other lesions, and HDR factors also protect stalled replication forks. As a result, loss of BRCA1 or BRCA2 poses significant risks to genome integrity, leading not only to cancer predisposition but also to sensitivity to DNA-damaging agents, affecting therapeutic approaches. Here we review recent advances in our understanding of BRCA1 and BRCA2, including how they genetically interact with other repair factors, how they protect stalled replication forks, how they affect the response to aldehydes, and how loss of their functions links to mutation signatures. Importantly, given the recent advances with poly(ADP-ribose) polymerase inhibitors (PARPi) for the treatment of HDR-deficient tumors, we discuss mechanisms by which BRCA-deficient tumors acquire resistance to PARPi and other agents.

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