Homologous recombination and human health: the roles of BRCA1, BRCA2, and associated proteins.
Journal: 2016/January - Cold Spring Harbor perspectives in biology
ISSN: 1943-0264
Abstract:
Homologous recombination (HR) is a major pathway for the repair of DNA double-strand breaks in mammalian cells, the defining step of which is homologous strand exchange directed by the RAD51 protein. The physiological importance of HR is underscored by the observation of genomic instability in HR-deficient cells and, importantly, the association of cancer predisposition and developmental defects with mutations in HR genes. The tumor suppressors BRCA1 and BRCA2, key players at different stages of HR, are frequently mutated in familial breast and ovarian cancers. Other HR proteins, including PALB2 and RAD51 paralogs, have also been identified as tumor suppressors. This review summarizes recent findings on BRCA1, BRCA2, and associated proteins involved in human disease with an emphasis on their molecular roles and interactions.
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Cold Spring Harb Perspect Biol 7(4): a016600

Homologous Recombination and Human Health: The Roles of BRCA1, BRCA2, and Associated Proteins

Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065
Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, New York 10065
Correspondence:gro.ccksm.iks@nisaj-m
These authors contributed equally to this article.
Correspondence:gro.ccksm.iks@nisaj-m

Abstract

Homologous recombination (HR) is a major pathway for the repair of DNA double-strand breaks in mammalian cells, the defining step of which is homologous strand exchange directed by the RAD51 protein. The physiological importance of HR is underscored by the observation of genomic instability in HR-deficient cells and, importantly, the association of cancer predisposition and developmental defects with mutations in HR genes. The tumor suppressors BRCA1 and BRCA2, key players at different stages of HR, are frequently mutated in familial breast and ovarian cancers. Other HR proteins, including PALB2 and RAD51 paralogs, have also been identified as tumor suppressors. This review summarizes recent findings on BRCA1, BRCA2, and associated proteins involved in human disease with an emphasis on their molecular roles and interactions.

Abstract

Soon after homologous recombination (HR) was discovered to be an important DNA repair mechanism in mammalian cells, an association between HR deficiency and human disease was uncovered when the hereditary breast cancer suppressors BRCA1 and BRCA2 were found to be required for HR (Moynahan and Jasin 2010; King 2014). Subsequently, germline mutations in a number of other HR genes have been linked to tumor predisposition. Congenital defects have also been associated with impaired HR. Tumorigenesis can result from ongoing genomic instability from diminished repair, whereas developmental defects can arise from cell death/senescence. That HR genes act as genomic caretakers has generated widespread interest in both the scientific and medical communities. Because HR defects confer sensitivity to certain DNA-damaging agents, they are being exploited in cancer therapies. Drugs that cause synthetic lethality in the context of HR defects also hold promise for treatment (Bryant et al. 2005; Farmer et al. 2005). This review provides a brief overview of HR in mammalian cells and summarizes the molecular roles of BRCA1, BRCA2, and associated HR proteins involved in human disease. Extensive discussion of HR pathways can be found in Mehta and Haber (2014).

ACKNOWLEDGMENTS

We thank previous members of the Jasin Laboratory whose work is referenced in this review. This work is supported by National Institutes of Health {"type":"entrez-nucleotide","attrs":{"text":"GM110978","term_id":"221993159","term_text":"GM110978"}}GM110978 (to R.P.) and {"type":"entrez-nucleotide","attrs":{"text":"CA185660","term_id":"35124656","term_text":"CA185660"}}CA185660 and {"type":"entrez-nucleotide","attrs":{"text":"GM054668","term_id":"218108106","term_text":"GM054668"}}GM054668 (to M.J.).

ACKNOWLEDGMENTS

Footnotes

Editors: Stephen Kowalczykowski, Neil Hunter, and Wolf-Dietrich Heyer

Additional Perspectives on DNA Recombination available at www.cshperspectives.org

Footnotes

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