BRCA1: A locus-specific and genetic integrity "Liaison" in gene expression and genetic integrity

Mutations in BRCA1 predominantly lead to elevated risks of breast and ovarian cancers. In contrast to the tissue-specific nature of BRCA1 tumors, the normal BRCA1 gene product functions in diverse nuclear events including transcription, DNA repair, and DNA damage checkpoint. Recent findings of physical and function a I associations between BRCA1 and the RNA polymerase II (RNAPII)-dependent transcription machinery may shed some light on this longstanding paradox of BRCA1 biology. Eukaryotic gene expression is now known to be a continuous process, whereby each step is physically and functionally connected to the next. In particular, RNAPII plays a pivotal role in coordinating transcription with various pre-mRNA processing events and stress response. Interestingly, BRCA1 preferentially interacts with the processive form of RNAPII and proteins that regulate RNAPII activity and movement during transcription elongation. In response to DNA damage, BRCA1 dissociates from RNAPII and localizes to DNA damage sites. We propose that BRCA1 may coordinate multiple steps in gene expression, including transcription initiation, elongation, and pre-mRNA processing via its interactions with the transcription machinery at selected gene loci. The same BRCA1-associated transcription apparatus may serve as a sensor for stress signals and facilitate the transition from a transcription state to checkpoint/DNA repair state. Such a coordinating role of BRCA1 in gene expression may ensure the appropriate quantity and quality of the mature transcripts for certain breast and ovarian cancer-related genes, as well as the genetic integrity of the breast and ovary tissues. (c) 2005 Wiley-Liss, Inc.