The Hsp90 molecular chaperone system

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DESCRIPTION (provided by applicant): Our long-term objective is to understand the cellular breadth and impact of the Hsp90 molecular chaperone system. To dissect this large and diverse chaperone network we have exploited high-throughput approaches to identify genetic and physical interactors of the yeast p23 cochaperone Sba1, which serves one branch of the yeast Hsp90 (Hsp82) chaperone system. Unexpectedly, bioinformatic analysis indicates that the Sba1 subnet both overlaps with and is sovereign to the identified Hsp82 network. Notably, a significant share of the Sba1 hits function at or near DNA. Thus, Sba1 appears to extend the role of the Hsp82 system to a variety of nuclear events including transcription, chromatin, telomere and DNA repair pathways. We will focus on telomere and DNA repair paths to better understand how component ts of the Hsp90 system affect nuclear events. To investigate the influence of the Sba1 chaperone we will follow a three-pronged strategy in which a) in vivo assays will be utilized to establish the physiological effect of Sba1 on DNA-related activities; b) genetic phenotypes will be employed to identify functional sba1 alleles; c) the molecular mechanisms of chaperone-regulation on client proteins will be delineated using in vitro assays. Our studies will contribute to the comprehension of how the Hsp90 chaperone network maintains cellular proteostasis and how this broad chaperone system might be dissected by targeting cochaperones to develop more selective therapeutic strategies that are directed at the Hsp90 machinery.