Objective Cockayne syndrome is a congenital disease with impaired DNA repair in actively transcribed genes. Affected children show developmental abnormalities and signs of premature aging. Cockayne syndrome is caused by mutations in the Cockayne syndrome complementation group A (CSA) and B (CSB) genes. While CSB encodes a SWI/SNF ATPase that likely assists the stalled RNA polymerase in overcoming lesions, CSA’s detailed role in repair has so far remained elusive. CSA is part of the DDB1-CSA-Cul4-Rbx1 E3 ubiquitin ligase complex. The available data suggest that CSA may function as a substrate adaptor for ubiquitination by the DDB1-Cul4-Rbx1 ligase.I will pursue a novel structure-driven proteomic approach to identify the substrate epitope recognized by the DDB1-CSA-Cul4-Rbx1 E3 ubiquitin ligase. These experiments aim to provide the important missing signal required for recruitment of the ligase complex to sites of stalled RNA polII complexes. Importantly, the CSA ligase, as it arrives at sites of DNA damage, is inactive. Our comprehensive structural and biochemical efforts will thus include the mechanisms of regulation of the CSA ubiquitin ligase activity by activators and inhibitors following recruitment to the repair site.MoBa-CS will not only improve our understanding of CSA’s molecular role in Cockayne syndrome, but also reveal CSA’s mode of action within the essential transcription coupled repair pathway. Understanding the cellular signals overseeing transcription coupled repair will provide important insights into how the pathway is integrated within the overall DNA damage response circuitry of the cell. ERC funding would enable us to pursue an interdisciplinary proteomic and structure based approach in examining DDB1-CSA function. Fields of science natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsproteomicsnatural sciencesbiological sciencesgeneticsDNAnatural sciencesbiological sciencesgeneticsmutationnatural sciencesbiological sciencesgeneticsRNA Programme(s) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Topic(s) ERC-SG-LS1 - ERC Starting Grant - Molecular and Structural Biology and Biochemistry Call for proposal ERC-2010-StG_20091118 See other projects for this call Funding Scheme ERC-SG - ERC Starting Grant Host institution FRIEDRICH MIESCHER INSTITUTE FOR BIOMEDICAL RESEARCH FONDATION EU contribution € 1 499 235,00 Address MAULBEERSTRASSE 66 4058 Basel Switzerland See on map Region Schweiz/Suisse/Svizzera Nordwestschweiz Basel-Stadt Activity type Research Organisations Principal investigator Nicolas Thomä (Dr.) Administrative Contact Searles Dorothy (Mrs.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data Beneficiaries (2) Sort alphabetically Sort by EU Contribution Expand all Collapse all FRIEDRICH MIESCHER INSTITUTE FOR BIOMEDICAL RESEARCH FONDATION Switzerland EU contribution € 1 499 235,00 Address MAULBEERSTRASSE 66 4058 Basel See on map Region Schweiz/Suisse/Svizzera Nordwestschweiz Basel-Stadt Activity type Research Organisations Principal investigator Nicolas Thomä (Dr.) Administrative Contact Searles Dorothy (Mrs.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data Novartis Forschungsstiftung Switzerland EU contribution No data Address Maulbeerstrasse 66 4058 BASEL See on map Activity type Research Organisations Administrative Contact Dorothy Searles (Ms.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data
