Regulatory Mechanisms in Transcriptional Activation by BRCA1

摘要

In our original proposal we presented preliminary evidence suggesting a critical region for the modulation of BRCA1's transactivation activity and proposed the existence of an intramolecular interaction domain that masks the activation domain of BRCA1, thus impairing the recruitment of the machinery involved in transcription initiation. Our hypothesis was that BRCA1 transcriptional function is regulated by an auto inhibitory intramolecular interaction between regions encoded by exon 12 (and possibly part of exon 13) and the C-terminal region comprising the BRCT domains. We suggested that this mechanism might form the basis of the regulation of transcriptional activation by BRCA1. Our expectation was that a region that interacts and masks the activation domain would be identified in detail and would reveal one of the means by which BRCAl activity is regulated. During the past four years the experiments performed seem to refute our original hypothesis. At this point, the experiments conducted here have refuted our initial hypothesis of a regulatory role for an intramolecular interaction in BRCA1. Nevertheless, the experiments revealed that a putative coiled-coil domain spanning exons 12 and 13 is important for transcription regulation.