The Impact of mutation-induced mislocalization of BRCA1 on nuclear function

Inherited mutations in the human BRCA1 gene confer increased susceptibility to early onset breast and ovarian cancer. Biochemical and cell biological data suggest that BRCA1 may act as a tumor suppressor protein by guarding genome stability; it was reported to play a role in DNA repair as well as in transcriptional activation. BRCA1 is most frequently located in the nucleus, but it has also been detected in the cytoplasm of breast and ovarian cancer cells. Recently, it was shown that BRCA1 can shuttle between the nucleus and cytoplasm. Several different BRCA1 breast cancer associated mutations were identified which have a dramatic effect on BRCA1 cellular distribution. The most intriguing effect was observed of short C-terminal truncations which completely abolished nuclear shuttling of BRCA1 and resulted in cytoplasmic localization. Many of the mutations tested are known to inactivate BRCA1 function in either transcription activation or DNA damage response. This proposal aims at investigating in detail the relationship between BRCA1 genetic mutations and their effect on cellular localization and function. Three main questions are to be answered: 1. Do the most frequent breast cancer mutations alter BRCA1 cellular location? 2. Does cytoplasmic mislocalization reduce BRCA1 nuclear activity in breast cancer cells? 3. Is it possible to correct the functional defects by modifying BRCA1 location?