BRCA1 16 years later: nuclear import and export processes.

Over the past several years, the importance of regulated nuclear transport processes for tumor suppressors has become evident. Proteins with a molecular mass greater than 40 kDa can enter the nucleus only by active transport across the nuclear membrane. The most common pathway by which this occurs is via the importin alpha/beta pathway, whereby the cargo protein binds importin alpha. This heterodimer binds importin beta and the heterotrimer passes through nuclear pores at the expense of GTP. Breast cancer susceptibility gene 1 (BRCA1) is one such protein. As a mediator of transcription and DNA repair, two exclusively nuclear functions, BRCA1, at 220 kDa, can enter the nucleus only via active transport mechanisms. In addition to the classical importin alpha/beta pathway, BRCA1 can also enter the nucleus in a piggyback mechanism with BRCA1-associated RING domain protein 1 (BARD1). The interaction between BRCA1 and BARD1 is also important in the retention of BRCA1 in the nucleus. This is important because BRCA1 also undergoes active nuclear export. BRCA1 is also involved in apoptotic processes. Whether this occurs within the nucleus or cytoplasm is still unclear; thus, the consequences of BRCA1 nuclear export have not been clearly elucidated. This review will discuss the literature regarding the subcellular localization of BRCA1, with particular emphasis on its nuclear import and export processes.