Linking proteasome activity to DNA repair through hHR23

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DESCRIPTION (provided by applicant): We propose to investigate the mechanism by which the proteasome functions in DNA repair by revealing the structure and dynamics of the proteins that are instrumental in linking these two pathways. The proteasome is a renowned protein degradation machinery and nucleotide excision repair is the major process responsible for repairing UV-damaged DNA. Much evidence has recently established that proteasome activity is important for nucleotide excision repair as mediated via the hHR23 family of proteins (hHR23a and hHR23b). HHR23 proteins contain four structured domains, each of which interacts with a different binding partner. Ongoing studies reveal that hHR23 proteins undergo global structural changes upon associating with the proteasome. The proposed research uses NMR spectroscopy to further investigate the structure and dynamics of hHR23a alone and with components of the ubiquitin-proteasome pathway. NMR is the best method for studying molecular motions and protein-protein interactions and our findings have resulted in a model for how the proteasome functions through hHR23 proteins in nucleotide excision repair. Based on our structural data, we design mutated constructs to test our model in vivo with functional assays. This work is expected to yield fundamental knowledge of the mechanism behind the hHR23 interaction with the ubiquitin-proteasome pathway and how this interaction functions in nucleotide excision repair.