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.
| Howe, Rebecca; Miron-Shatz, Talya; Hanoch, Yaniv et al. (2015) Personalized Medicine Through SNP Testing for Breast Cancer Risk: Clinical Implementation. J Genet Couns 24:744-51 |
| Hanoch, Yaniv; Miron-Shatz, Talya; Rolison, Jonathan J et al. (2015) Shared decision making in patients at risk of cancer: the role of domain and numeracy. Health Expect 18:2799-810 |
| Ehlinger, Aaron; Walters, Kylie J (2013) Structural insights into proteasome activation by the 19S regulatory particle. Biochemistry 52:3618-28 |
| Ehlinger, Aaron; Park, Soyeon; Fahmy, Amr et al. (2013) Conformational dynamics of the Rpt6 ATPase in proteasome assembly and Rpn14 binding. Structure 21:753-65 |
| Randles, Leah; Walters, Kylie J (2012) Ubiquitin and its binding domains. Front Biosci (Landmark Ed) 17:2140-57 |
| Chen, Xiang; Walters, Kylie J (2012) Identifying and studying ubiquitin receptors by NMR. Methods Mol Biol 832:279-303 |
| Liu, Fen; Walters, Kylie J (2011) Policing Parkin with a UblD. EMBO J 30:2757-8 |
| Neklason, Deborah W; Done, Michelle W; Sargent, Nykole R et al. (2011) Activating mutation in MET oncogene in familial colorectal cancer. BMC Cancer 11:424 |
| Liu, Fen; Walters, Kylie J (2010) Multitasking with ubiquitin through multivalent interactions. Trends Biochem Sci 35:352-60 |
| Chen, Xiang; Lee, Byung-Hoon; Finley, Daniel et al. (2010) Structure of proteasome ubiquitin receptor hRpn13 and its activation by the scaffolding protein hRpn2. Mol Cell 38:404-15 |
Showing the most recent 10 out of 29 publications
