Evidence for a transcriptional activation function of BRCA1 C-terminal region

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Abstract
Mutations in BRCA1 account for 45% of families with high incidence of breast cancer and for 80–90% of families with both breast and ovarian cancer. BRCA1 protein includes an amino-terminal zinc finger motif as well as an excess of negatively charged amino acids near the C terminus. In addition, BRCA1 contains two nuclear localization signals and localizes to the nucleus of normal cells. While these features suggest a role in transcriptional regulation, no function has been assigned to BRCA1. Here, we show that the C-terminal region, comprising exons 16–24 (aa 1560–1863) of BRCA1 fused to GAL4 DNA binding domain can activate transcription both in yeast and mammalian cells. Furthermore, we define the region comprising exons 21–24 (aa 1760–1863) as the minimal transactivation domain. Any one of four germ-line mutations in the C-terminal region found in patients with breast or ovarian cancer (Ala-1708 → Glu, Gln-1756 C+, Met-1775 → Arg, Tyr-1853 → Stop), had markedly impaired transcription activity. Together these data underscore the notion that one of the functions of BRCA1 may be the regulation of transcription.