Cancer Genetics

Edited by: Paul Smaglik and Eugene Russo R. Scully, J.J. Chen, A. Plug, Y.H. Xiao, D. Weaver, J. Feunteun, T. Ashley, D.M. Livingston, "Association of BRCA1 with Rad51 in mitotic and meiotic cells," Cell, 88:265-75, Jan. 24, 1997. (Cited in more than 235 papers since publication) Comments by David M. Livingston, Emil Frei professor of genetics and medicine, Harvard Medical School, and chairman of the executive committee for research, Dana-Farber Cancer Institute David M. Livingston The tumor-suppressing ability of the infamous BRCA1 gene--which, along with BRCA2, has been linked to breast cancer1,2--was a complete mystery prior to the findings reported in this paper. Some had speculated that the gene's product served as a growth factor or a hormone. Senior author David M. Livingston and his colleagues at Harvard were the first to give some definitive indication as to where the gene might fit into the biochemical pathway that leads to breast cancer onset. The Harvard investigators found that the product of BRCA1, known to suppress the development of the earlier-than-normal onset of breast and ovarian cancer, spends at least some part of its working life interacting with the protein Rad51. Rad51 had been identified previously, based on studies in other eukaryotes such as yeast, as one of a corps of molecules dedicated to repairing double-stranded DNA breaks and/or homologous recombination. The BRCA1-Rad51 interaction therefore implied that BRCA1 is involved in the pathways that maintain genomic integrity as well as normal chromosomal recombination, one of the most crucial processes during meiosis. "BRACA1 and Rad51 were found by us to decorate the surfaces of synaptanemal complexes--structures in the human spermatocytes actually in the process of carrying out meiotic recombination," explains Livingston. The presence of the BRCA1 protein on these structures, and its formation of stable biochemical complexes with Rad51 in mitotic cells, suggested to researchers that the two proteins were communicating with each another. Three months later, a team at Baylor University led by Allan Bradley made an observation3 analogous to that of the Harvard researchers'. They found that mouse BRCA2 could interact with Rad51; they also found that mouse embryos missing BRCA2 were hypersensitive to radiation. Those two observations together suggested that BRCA2 is also an essential cofactor in the Rad51-dependent DNA repair of double-strand breaks taking place during chromosomal recombination. According to Livingston, his findings and those of the Baylor team "got people to think along a different line than they'd thought before." Livingston's team followed up the initial research with an August 1997 paper in which they further explore, and confirm, BRCA1's involvement in a set of signaling pathways that begins with DNA damage and ends up with its repair.4 In another paper, the Harvard group demonstrates that BRCA1 and BRCA2 form a functional biochemical complex associated with double-strand break repair and/or homologous recombination.5 They suspect, based on these findings, that the dysfunction of this pathway may be indicative of the majority of cases of hereditary breast and/or ovarian cancer. "We're trying to probe the hypothesis and determine how accurate it is," says Livingston. "And assuming that it's accurate or inaccurate, [we're] trying to understand in great molecular detail how the protein works biochemically." He adds, though, that the top priority is to understand how the protein suppresses the development of breast cancer and ovarian cancer and why it doesn't seem to lead to diseases in other organs. Incorporating an understanding of the tumor suppressors' functional significance in the pathogenic pathway that leads to breast cancer is, says Livingston, a long way off. J.M. Hall et al., "Linkage of early-onset familial breast-cancer to chromosome-17Q21," Science, 250:1684-9, Dec. 21, 1990. D.F. Easton et al., "Genetic-linkage analysis in familial breast and ovarian cancer results from 214 families," American Journal of Human Genetics, 52:678-701, 1993. S.K. Sharan et al., "Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking BRCA2," Nature, 386:804-10, 1997. R. Scully et al., "Dynamic changes of BRCA1 subnuclear location and phosphorylation state are initiated by DNA damage," Cell, 90:425-35, 1997. J.J. Chen et al., "Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells," Molecular Cell, 2:317-28, September 1998.

Cancer Genetics

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