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

TLDR

Mutations in HDR genes such as BRCA1 and BRCA2 are common in breast, ovarian, prostate, and other cancers, and because HDR repairs double‑strand breaks and protects stalled replication forks, loss of these genes compromises genome integrity, increases cancer risk, and heightens sensitivity to DNA‑damaging therapies. This review surveys recent insights into BRCA1 and BRCA2 functions—including their genetic interactions, fork protection, aldehyde response, and mutation signatures—and examines how BRCA‑deficient tumors develop resistance to PARP inhibitors and other therapies. The authors synthesize current literature on BRCA1/2 biology and therapeutic resistance, integrating genetic interaction data, fork protection assays, aldehyde response studies, and mutation signature analyses to elucidate resistance mechanisms to PARP inhibitors.

Abstract

Germ-line and somatic mutations in genes that promote homology-directed repair (HDR), especially BRCA1 and BRCA2, 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.