A nuclear function for the tumor suppressor BRCAI

Abstract

The breast and ovarian cancer susceptibility gene BRCAl has been recently cloned and revealed an open reading frame of 1863 amino acids, but a lack of significant homology to any known protein in the database has led to few clues about its functions. One of the first steps to investigate the function of BRCAl was to define its subcellular localization. Several reports have led to contradictory findings that include: nuclear localization in normal cells and cytoplasmic in breast and ovarian cancer cells; nuclear in both normal and cancer cells; cytoplasmic and secreted to the extracellular space; present in tube-like invaginations of the nucleus; and colocalizing with the centrosome. As is apparent, the subcellular localization has been the most controversial aspect of BRCAl biology and is a key point to uncover its functions. In this paper we review the published data on subcellular localization of BRCAl with special emphasis on the antibodies and techniques used. We conclude that there is now overwhelming evidence to support a nuclear localization for BRCAl, both in normal and cancer cells. In addition, several BRCAl-interacting proteins have been isolated and they are preferentially located in the nucleus. Evidence supporting a physiological function for BRCAl during DNA repair and transcriptional activation is also discussed.