The Breast Cancer Susceptibility Gene BRCA1 Is Required for Subnuclear Assembly of Rad51 and Survival following Treatment with the DNA Cross-linking Agent Cisplatin*

By A. Bhattacharyya, Uy Ear, B. Koller, R. Weichselbaum, D. K. Bishop. 2000

631 citations recorded by the source corpus.

Mutations in breast cancer tumor susceptibility genes, BRCA1 and BRCA2, predispose women to early onset breast cancer and other malignancies. The Brca genes are involved in multiple cellular processes in response to DNA damage including checkpoint activation, gene transcription, and DNA repair. Biochemical interaction with the recombinational repair protein Rad51 (Scully, R., Chen, J., Ochs, R. L., Keegan, K., Hoekstra, M., Feunteun, J., and Livingston, D. M. (1997) Cell 90, 425–435), as well as genetic evidence (Moynahan, M. E., Chiu, J. W., Koller, B. H., and Jasin, M. (1999) Mol. Cell 4, 511–518 and Snouwaert, J. N., Gowen, L. C., Latour, A. M., Mohn, A. R., Xiao, A., DiBiase, L., and Koller, B. H. (1999) Oncogene 18, 7900–7907), demonstrates that Brca1 is involved in recombinational repair of DNA double strand breaks. Using isogenic Brca1 +/+and brca1 −/− mouse embryonic stem (ES) cell lines, we investigated the role of Brca1 in the cellular response to two different categories of DNA damage: x-ray induced damage and cross-linking damage caused by the chemotherapeutic agent, cisplatinum. Immunoflourescence studies with normal andbrca1 −/− mutant mouse ES cell lines indicate that Brca1 promotes assembly of subnuclear Rad51 foci following both types of DNA damage. These foci are likely to be oligomeric complexes of Rad51 engaged in repair of DNA lesions or in processes that allow cells to tolerate such lesions during DNA replication. Clonogenic assays show that brca1 −/− mutants are 5-fold more sensitive to cisplatinum compared with wild-type cells. Our studies suggest that Brca1 contributes to damage repair and/or tolerance by promoting assembly of Rad51. This function appears to be shared with Brca2.

Subfields: Genetics, Molecular Biology

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Citations in the corpus

EgoNet: identification of human disease ego-network modules (2014, background): “When applied to a triple-negative breast cancer (TNBC) microarray dataset, the top selected modules contain both known gene markers in TNBC and novel candidates, such as RAD51 and DOK1, which play a central role in their respective ego-networks by connecting many differentially expressed genes.”
Toward maintaining the genome: DNA damage and replication checkpoints. (2002, background): “For instance, the Rad51 recombination protein is not essential in yeast but it is in mammalian cells (194); perhaps mammalian and yeast genomes incur the same number of breaks per unit of DNA, but the mere fact that the mammalian genome is 250 times larger than the yeast genome makes repair proteins”
Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy (2005, result): “This latter finding is consistent with previous observations that agents that cause recombinogenic lesions do not induce formation of RAD51 foci in BRCA1- or BRCA2-deficient cell”
Insights into molecular classifications of triple-negative breast cancer: improving patient selection for treatment (2019, background): “, platinum, mitomycin C) or PARP inhibitors, cause persistent DNA damage in HR-deficient cells and, consequently, induction of cell-cycle arrest and apoptosis (76, 77).”
53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks (2010, neutral): “To test this, we first examined Rad51 foci formation, a marker of HR, which is impaired in Brca1 mutant cells (Bhattacharyya et al., 2000; Scully et al., 1997).”
The roles of BRCA1 and BRCA2 and associated proteins in the maintenance of genomic stability (2006, background): “The involvement of BRCA1 in the repair of DSBs by GC is consistent with its association and colocalization with RAD51 in nuclear foci, and, accordingly, BRCA1 is required for their formation (Bhattacharyya et al., 2000).”
NEW STRATEGIES FOR TRIPLE NEGATIVE BREAST CANCER – DECIPHERING THE HETEROGENEITY (2014, background): “of the Fanconi anemia–BRCA1 pathway are more sensitive to X-ray–induced damage and DNA cross-linking agents such as cisplatin (20, 22).”
DNA interstrand crosslink repair and cancer (2011, neutral): “RAD51-deficient cells, like the tumour cell lines derived from patients with BRCA1 and BRCA2 alterations, are hypersensitive to ICL-inducing agent”
BRCA2 is required for homology-directed repair of chromosomal breaks. (2001, background): “These cell lines cated that Rad51 levels were similar in Brca21/1 and are mutant for Brca1 (Moynahan et al., 1999; Bhattacharyya et al., 2000), Rad54 (Tan et al., 1999; DronkertBrca2lex1/lex2 cells, and that it was distributed in both the et al., 2000), and the Rad51-related protein XRCC3nucleus…”