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Program Project in Structural Cell Biology of DNA Repair Machines: Project 3: DNA Double-Strand Break Repair (DSBR)

Performance Sites

UC / Lawrence Berkeley National Laboratory 1 Cyclotron Road Life Sciences Division, Building 74 Berkeley, CA 94720
Baylor College of Medicine Department of Biochemistry & Cell Biology Room N403 One Baylor Plaza Houston, TX 77030
University of Maryland School of Medicine Radiation Oncology Research Laboratory Bressler Research Building, 6-015 655 West Baltimore Street Baltimore, MD 21201

Key Personnel

NameOrganizationRole on Project
Tainer, John A. UC / Lawrence Berkeley National Laboratory Principal Investigator; Project 3 Leader; SCB Core Director
Carney, James P. University of Maryland School of Medicine Project 3 Senior Investigator
Chen, David J. UC / Lawrence Berkeley National Laboratory Project 3 Senior Investigator
Qin, Jun Baylor University Project 3 Senior Investigator
Campisi, Judith UC / Lawrence Berkeley National Laboratory Collaborator

Links to web sites:

SBDR Project 3 Abstract

DNA double strand breaks (DSBs) are a particularly severe and mutagenic form of DNA damage as they disrupt genetic continuity. Proteins involved in prevention and repair of DSBs are associated with a variety of severe human diseases, such as breast and ovarian cancer (BRCA1 and BRCA2), Nijmegen Breakage Syndrome (NBS1), Bloom's syndrome (BLM), Ataxia telangiectasia (Mre11) and premature aging (WRN). In this project we aim to understand, at the molecular level, early events of DSB repair (DSBR) such as DSB recognition and processing, DSBR by nonhomologous end joining (NHEJ), and DSB prevention by RecQ family helicases. Research of the past years revealed that proteins involved in DSBR often not only interact with each other and other DNA repair proteins but exist in large superassemblies or repairosomes. The resulting complexity of protein-protein interactions and of conformational switches makes it necessary to shift efforts to understand the underlying molecular events, from the analysis of individual components, as has been successfully performed in the past, to the study of complexes and super-assemblies. For that reason, we propose to elucidate molecular events of protein-protein interactions, assembly states and conformational switching, for early events in DSBR. Tight synergies with Projects 4 (Homologous Recombination Repair) and 5 (Mismatch Repair Interactions), plus collaborative efforts within this Program Project, will ensure the required experimental innovations, aided by advance technologies for protein expression and protein characterization techniques (EMB Core) and for the structure determination of large complexes (SCB Core). We will begin to understand the complex nature of DSBR conformational switching and interactions by focusing on five Specific Aims: Aim 1 will study functional and structural switches in the NHEJ machinery in response to phosphorylation; Aim 2 will study the structure and function of the Rad50/BRCA1 interaction; Aim 3 will study the modulation of end processing of the Rad50/Mre11/Nbs1 complex by RPA; Aim 4 will study the structure and function of DSB preventive RecQ helicases; and Aim 5 will study early temporal and spatial interaction of DSBR factors by chromatin immunoprecipitation. The anticipated combined outcome of the proposed five specific Aims will be a molecular picture of protein-protein interactions and functional states orchestrating early events of DSBR. This picture will provide the molecular foundation for a detailed understanding of human diseases and cancer predispositions linked to DSBR proteins.
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