BRCA gene structure and function in tumor suppression: a repair-centric perspective.
Germline mutations in the BRCA1 and BRCA2 genes are characterized by deficient repair of DNA double-strand breaks by homologous recombination. Defective DNA double-strand break repair has been not only implicated as a key contributor to tumorigenesis in mutation carriers but also represents a potential target for therapy. The transcriptional similarities between BRCA1-deficient tumors and sporadic tumors of the basal-like subtype have led to the investigation of homologous recombination repair-directed therapy in triple-negative tumors, which demonstrates overlap with the basal-like subtype. We broaden the scope of this topic by addressing a "repair-defective" rather than "BRCA1-like" phenotype. We discuss structural and functional aspects of key repair proteins including BRCA1, BRCA2, BRCA1 interacting protein C-terminal helicase 1, and partner and localizer of BRCA2 and describe the phenotypic consequences of their loss at the cellular, tissue, and organism level. We review potential mechanisms of repair pathway dysfunction in sporadic tumors and address how the identification of such defects may guide the application of repair-directed therapies.
Murphy
Conleth G
CG
Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center, New York City, NY 10065, USA.
Moynahan
Mary Ellen
ME
D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D024682:BRCA2 Protein / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004260:DNA Repair / Q000235:genetics*; D005260:Female; D016147:Genes, Tumor Suppressor; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D011379:Prognosis
D019313:BRCA1 Protein; D024682:BRCA2 Protein