Affiliation:
1. Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065;,
2. Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY 10065
3. Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065
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.
Subject
Cancer Research,Cell Biology,Oncology
Cited by
221 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献