BRCA1, BRCA2, and DNA Damage Response: Collision or Collusion?

study by Patel et al. (1998) in the February issue of Introduction Molecular Cell provides additional evidence of a role for While the isolation of the breast cancer susceptibility BRCA2 in response to DNA damage, by examining the genes BRCA1 and BRCA2 generated considerable mephenotype of cells derived from mice homozygous for dia and scientific interest, the nucleotide sequence of a truncated allele of BRCA2. these genes did not yield much insight into their biologiBRCA1, BRCA2, and RAD51 cal roles. Efforts to elucidate their function have been Several lines of evidence have led investigators to posfraught with the difficulties inherent in working with large tulate a role for BRCA1 and BRCA2 in response to DNA molecules that alter the growth characteristics of cells damage. These include: (1) colocalization of BRCA1, and, in the case of BRCA1, significant controversy over BRCA2, and RAD51; (2) similarities in the chromosomal data as fundamental as the subcellular compartmentalabnormalities seen following disruption of Rad51 and ization of the protein. However, several recent reports BRCA2; and (3) the role of RAD51 in recombination, DNA have provided insight into the cellular pathways that repair, and chromosome maintenance. Additionally, the may be affected by alterations in BRCA1 and BRCA2 mammalian tissue expression pattern of Rad51 is very (Connor et al., 1997; Scully et al., 1997a, 1997b, 1997c; similar to that of BRCA1 and BRCA2, with high-level Sharan et al., 1997; Patel et al., 1998), and cellular reexpression primarily in testes and thymus, as might be sponse to DNA damage is a consistent theme. expected of genes important in meiosis and recombinaBRCA1 and BRCA2 Have Numerous Similarities tion, respectively (Friedberg et al., 1995; Rajan et al., BRCA1 and BRCA2 were localized to regions on chro1997). mosome 17 and 13, respectively, using genetic linkage In order to understand how BRCA1 and BRCA2 might in families with multiple breast and/or ovarian cancers. be acting in the response to DNAdamage, it is instructive Mutations in these genes increase breast cancer risk to to firstexamine what isknown about RAD51 fromseveral carriers by 15to 20-fold over the general population species. hRAD51 catalyzes ATP-dependent DNA strand risk. BRCA1 and BRCA2 behave as classic tumor supexchange reactions and is one of at least five human pressor genes, in which loss of both alleles is required homologs of the prototypical E. coli recombination and for the initiation of malignancy. Furthermore, they enrepair protein RecA. The yeast S. cerevisiae has a similar code nuclear proteins with a cell-cycle regulated exset of RecA homologs that function in normal meiotic pression pattern that colocalize in multiple tissues durand mitotic recombination, DNA damage repair, and ing proliferation and differentiation (Rajan et al., 1997). chromosome segregation (Friedberg et al., 1995; Lim BRCA1 and BRCA2 also both contain putative transcripand Hasty, 1996; and references therein). The homology tional activation domains (Chapman and Verma, 1996; of RecA-related proteins is functional as well as strucMilner at al., 1997). Mice with targeted disruptions of tural, with the mouse Rad51 cDNA able to complement the 59 end of BRCA1 or BRCA2 die early in embryonic the S. cerevisiae rad51 deletion mutant. However, the development with evidence of reduced cellular proliferaphenotypic effects of Rad51 deletion in different organtion and increased expression of p21; these mouse emisms highlights the difficulties inherent in cross-species bryos survive several days longer in a p53or p21-null comparisons. S. cerevisiae rad51 deletion mutants are background (Ludwig et al., 1997, and references thereviable and exhibit sensitivity to UVand g-irradiation as in). Finally, no somatic mutations of either BRCA1 or well as monofunctional alkylating agents, with a defiBRCA2 have been identified in sporadic breast cancers. ciency in mitotic homologous recombination (which is The first hint that BRCA1 and BRCA2 may be comporequired for double-strand break repair in yeast), and a nents of DNA damage response pathways came from meiotic block that results in an inability to produce viable their association with human RAD51 (hRAD51; Scully et spores. By contrast, deletion of Rad51 in mice is an al., 1997a;Sharan et al.,1997; Wong, et al.,1997). BRCA2 early embryonic lethal defect, suggesting a role in prolifappears to interact directly with hRAD51, through at eration as well as recombination and repair (Lim and least two binding sites—one in the N-terminal end of the Hasty, 1996). In fact, the inability to generate Rad512/2