RAD51 up-regulation bypasses BRCA1 function and is a common feature of BRCA1-deficient breast tumors - PubMed (original) (raw)
RAD51 up-regulation bypasses BRCA1 function and is a common feature of BRCA1-deficient breast tumors
Richard W Martin et al. Cancer Res. 2007.
Free article
Abstract
The breast cancer susceptibility gene BRCA1 encodes a large protein thought to contribute to a variety of cellular processes, although the critical determinants of BRCA1-deficient tumorigenesis remain unclear. Given that BRCA1 is required for cell proliferation, suppressor mutations are believed to modify BRCA1 phenotypes and contribute to the etiology of BRCA1-deficient tumors. Here, we show that overexpression of the homologous recombinase RAD51 in a DT40 BRCA1Delta/Delta mutant rescues defects in proliferation, DNA damage survival, and homologous recombination (HR). In addition, epistasis analysis with BRCA1 and the DNA end-joining factor KU70 indicates that these factors operate independently of one another to repair double-strand breaks. Consistent with this genetic finding, cell synchronization studies show that the ability of BRCA1 to promote radioresistance is restricted to the late S and G2 phases of the cell cycle, as predicted for genes whose function is specific to homology-mediated repair rather than nonhomologous end-joining. Notably, retrospective analyses of microarray expression data reveal elevated expression of RAD51 and two of its late-acting cofactors, RAD54 and RAD51AP1, in BRCA1-deficient versus sporadic breast tumors. Taken together, our results indicate that up-regulation of HR provides a permissive genetic context for cells lacking BRCA1 function by circumventing its requirement in RAD51 subnuclear assembly. Furthermore, the data support a model in which enhanced HR activity contributes to the etiology of BRCA1-deficient tumors.
Similar articles
- Clinicopathological significance of KU70/KU80, a key DNA damage repair protein in breast cancer.
Alshareeda AT, Negm OH, Albarakati N, Green AR, Nolan C, Sultana R, Madhusudan S, Benhasouna A, Tighe P, Ellis IO, Rakha EA. Alshareeda AT, et al. Breast Cancer Res Treat. 2013 Jun;139(2):301-10. doi: 10.1007/s10549-013-2542-x. Epub 2013 Apr 28. Breast Cancer Res Treat. 2013. PMID: 23624778 - Genetic steps of mammalian homologous repair with distinct mutagenic consequences.
Stark JM, Pierce AJ, Oh J, Pastink A, Jasin M. Stark JM, et al. Mol Cell Biol. 2004 Nov;24(21):9305-16. doi: 10.1128/MCB.24.21.9305-9316.2004. Mol Cell Biol. 2004. PMID: 15485900 Free PMC article. - Caretaker Brca1: keeping the genome in the straight and narrow.
Yu V. Yu V. Breast Cancer Res. 2000;2(2):82-5. doi: 10.1186/bcr37. Epub 2000 Feb 7. Breast Cancer Res. 2000. PMID: 11250695 Free PMC article. Review. - The role of the BRCA1 tumor suppressor in DNA double-strand break repair.
Zhang J, Powell SN. Zhang J, et al. Mol Cancer Res. 2005 Oct;3(10):531-9. doi: 10.1158/1541-7786.MCR-05-0192. Mol Cancer Res. 2005. PMID: 16254187 Review.
Cited by
- Contribution of Radiation Sensitive Protein 51 Genotypes to Pterygium Risk in a Taiwanese Population.
Hsia NY, Hu PS, Chuang CL, Mong MC, Chen HC, Tsai CW, Wang YC, Chen JC, Bau DT, Chang WS. Hsia NY, et al. In Vivo. 2024 Sep-Oct;38(5):2197-2204. doi: 10.21873/invivo.13683. In Vivo. 2024. PMID: 39187312 Free PMC article. - SOSTDC1 Nuclear Translocation Facilitates BTIC Maintenance and CHD1-Mediated HR Repair to Promote Tumor Progression and Olaparib Resistance in TNBC.
Deng Q, Qiang J, Liu C, Ding J, Tu J, He X, Xia J, Peng X, Li S, Chen X, Ma W, Zhang L, Jiang YZ, Shao ZM, Chen C, Liu S, Xu J, Zhang L. Deng Q, et al. Adv Sci (Weinh). 2024 Aug;11(29):e2306860. doi: 10.1002/advs.202306860. Epub 2024 Jun 12. Adv Sci (Weinh). 2024. PMID: 38864559 Free PMC article. - [Research Advances of RAD51AP1 in Tumor Progression and Drug Resistance].
Liu R, Li M, Hu Z, Song Z, Chen J. Liu R, et al. Zhongguo Fei Ai Za Zhi. 2023 Sep 20;26(9):701-708. doi: 10.3779/j.issn.1009-3419.2023.102.34. Zhongguo Fei Ai Za Zhi. 2023. PMID: 37985156 Free PMC article. Review. Chinese. - The proofreading exonuclease of leading-strand DNA polymerase epsilon prevents replication fork collapse at broken template strands.
Ahmad T, Kawasumi R, Taniguchi T, Abe T, Terada K, Tsuda M, Shimizu N, Tsurimoto T, Takeda S, Hirota K. Ahmad T, et al. Nucleic Acids Res. 2023 Dec 11;51(22):12288-12302. doi: 10.1093/nar/gkad999. Nucleic Acids Res. 2023. PMID: 37944988 Free PMC article. - Finding significance: New perspectives in variant classification of the RAD51 regulators, BRCA2 and beyond.
Rein HL, Bernstein KA. Rein HL, et al. DNA Repair (Amst). 2023 Oct;130:103563. doi: 10.1016/j.dnarep.2023.103563. Epub 2023 Aug 19. DNA Repair (Amst). 2023. PMID: 37651978 Free PMC article. Review.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Research Materials
Miscellaneous