BRCA1 and the regulation of chromatin dynamics in gene expression

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Project Summary BRCA1 is an established tumor suppressor that plays a critical role in the development of both sporadic and hereditary breast and ovarian cancer. Considered a “master regulator” of genome integrity, BRCA1 has been linked to nearly all aspects of chromatin biology. Loss of BRCA1 is embryonic lethal and leads to cellular defects in stress signaling, DNA repair, cell cycle progression, apoptosis, chromatin condensation, and gene expression. Each of these processes involves dynamic changes in chromatin architecture that regulate spatial and temporal access to genomic DNA. Although implicated in various mechanisms of chromatin modification and remodeling, a mechanistic understanding of BRCA1’s role in regulating chromatin dynamics has been difficult to establish due to the global consequences of its dysfunction. Recently, we established a cell-free system that supports transcription of naturally chromatinized plasmid substrates in Xenopus egg extract. Transcriptional activity in extract is tightly coupled to changes in chromatin modification and structure, providing a powerful tool to study how regulation of chromatin dynamics controls gene expression. By coupling this system with established approaches used to elucidate mechanisms of DNA replication and DNA repair, we are now poised to examine the interplay between these fundamental processes. Indeed, BRCA1’s role as a sensor for genomic stress places it at the center of genome utilization, maintenance, and repair. In this proposal, we seek to understand how BRCA1 and other chromatin regulators control access to DNA in response to different cellular events. Together, these studies will provide new mechanistic insight into the complexities of chromatin signaling that remain an essential, but poorly understood regulator of genome integrity.