BRCA1 regulation and DNA damage: A biochemical and genetic analysis

Germline mutations to BRCA1 account for approximately 30% of familial breast cancer, with carriers having up to an 80-90% lifetime cancer risk (Easton et al. 1993). Breast tumors are diagnosed in BRCA1-mutation carriers who lose function of the wild type allele, leading to the hypothesis that BRCA1 may function as a classic tumor suppressor gene (Lindblom et al. 1993). Much recent work (reviewed in Zhang et al. 1998b) suggests that BRCA1 plays a role in the recognition and/or repair of DNA damage. First, we demonstrated that immediately after UVC exposure BRCA1 protein levels, as detected on a Western blot, increase in a time- and dose-dependent manner after UV-exposure. Pre-irradiation BRCA1 levels were higher than in unirradiated controls as early as 5 minutes after UVC exposure. We found no physical evidence that BRCA1 was stabilized following radiation, but BRCA1 transcript levels increased above baseline levels within 15 minutes of UVC treatment. We propose BRCA1 may be tightly bound to nuclear structures before UV exposure and is released from these complexes very early after damage occurs. Later accumulations of BRCA1 may be due to new protein production. Secondly, we demonstrated that BRCA1 mutation carriers who have short repeat-length polymorphisms within the XRCC1 3′UTR are less likely to develop breast cancer than those with longer alleles. Longer alleles were associated with an increased risk of cancer diagnosis but not with an altered age of disease onset. We also observed an association between Jewish ethnicity and presence of a single base pair substitution in exon 6 of XRCC1. We demonstrated that Jewish patients with the substitution had a decreased relative risk and a decreased observed age of disease onset than patients with wild-type alleles. No predictive associations were observed in non-Jewish patients. Given our data, and all the published information pertinent to BRCA1 to date, we developed a model of how BRCA1 functions in the cell. We hypothesize that BRCA1 is an important sensor for genomic integrity