Gene-specific Mechanisms of BRCA1 transcriptional Control

Division Of Basic Sciences - Nci

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Abstract

ACCOMPLISHMENTS 1) We have found that BRCA1 negatively regulates it own transcription by direct association with its promoter. Genotoxic stress and cell cycle progression cause a release of BRCA1 from the BRCA1 promoter that is associated with relief of repression.. 2) By ChiP/Chip we have identified numerous BRCA1-associated genes that play a role in cell cycle regulation, DNA repair, and chromatin structure and imply that BRCA1 could be a master transcriptional switch in control of genome stability. 3) We have identified a BRCA1 associated signature by ChIP/Chip that can predict poor clinical outcome in breast cancer patients. 4) Recent data indicates that is mode of regulation is universal and occurs in different cell types including breast and prostate. 5) We have begun to define the mechanism of association BRCA1 with its own promoter and have found the BRCA1 is assembled at its own promoter in a complex with E2F-1 and Rb that is release or disassembled in response to genotoxic stress. The disassembly of the complex is associated with an increase in transcriptional elongation of RNA polymerase II at the BRCA1 promoter indicating the a major role of BRCA1 in the control of gene expression may occur through the repression of transcriptional elongation.