This integrate multi-institutional Program Project in Structural Biology of DNA Repair (SBDR) addresses the challenge of understanding at the molecular level the pathways controlling genetic integrity. SBDR will a) produce biologically relevant DNA repair protein structures, b) identify fundamental structural principles for repair proteins, and c) provide the structural framework for a unified understanding of the biochemistry, genetics and biology needed for this field. SBDR will leverage and integrate the existing biological and structural research strengths and programs of the investigators and their institutions to develop, test, and promote a new paradigm for optimizing inter-disciplinary scientific collaborations in the post-genomic era. The structural biology of individual proteins is linked to complexes and pathways through five interconnecting Projects investigating key DNA repair processes: 1) base excision repair, 2) transcription-coupled and replication-associated base excision repair, 3) double-strand break detection and rejoining, 4) homozygous recombinatorial repair, and 5) mismatch repair. The resulting biologically driven determinations of repair protein structures will apply the comparative knowledge of the sequenced bacterial, archael, yeast, and human genomes to an understanding of the structural cell biology of DNA repair in man. LBNL will provide the center for unified research efforts by SBDR through three Cores: Expression and Molecular Biology, Structural Cell Biology, and Administrative. Together, these Cores will insure efficient application and coordination of methodological, technical, and scientific advances by the five component Projects. Quantitative characterization of dynamic conformations plus coupled high and low-resolution X-ray diffraction studies at the new SIBYLS synchrotron beamline at LBNL will integrate DNA repair biology with structure at escalating levels of complexity from domains to multi-protein molecular machines. As an integrated whole, SBDR addresses three unifying hypotheses: 1) DNA repair proteins function as a chemo-mechanical devices that detect and repair damage via protein and DNA conformational switching; 2) DNA repair proteins interact dynamically to form multi-protein macromolecular machines that utilize cooperatively and allostery to coordinate and regulate function; and 3) structurally-encoded interactions and pathway connections are as important as chemistry for biological function of repair proteins. The large macromolecular recognition interfaces thus identified are likely to contain more sequence polymorphisms than smaller, functionally, critical , active site regions. SBDR Program results will therefore be fundamental to rational deign of epidemiological studies and will provide the logical next step to fully utilizing the information on individual polymorphisms in DNA repair proteins developed by the DOE and NIH Environmental and Human Genome Project.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA092584-04
Application #
6791329
Study Section
Subcommittee G - Education (NCI)
Program Officer
Pelroy, Richard
Project Start
2001-09-27
Project End
2006-08-31
Budget Start
2004-09-01
Budget End
2005-08-31
Support Year
4
Fiscal Year
2004
Total Cost
$3,300,396
Indirect Cost
Name
Lawrence Berkeley National Laboratory
Department
Biophysics
Type
Organized Research Units
DUNS #
078576738
City
Berkeley
State
CA
Country
United States
Zip Code
94720
Sengupta, Shiladitya; Yang, Chunying; Hegde, Muralidhar L et al. (2018) Acetylation of oxidized base repair-initiating NEIL1 DNA glycosylase required for chromatin-bound repair complex formation in the human genome increases cellular resistance to oxidative stress. DNA Repair (Amst) 66-67:1-10
Mu, Hong; Geacintov, Nicholas E; Broyde, Suse et al. (2018) Molecular basis for damage recognition and verification by XPC-RAD23B and TFIIH in nucleotide excision repair. DNA Repair (Amst) :
Chavez, Diana A; Greer, Briana H; Eichman, Brandt F (2018) The HIRAN domain of helicase-like transcription factor positions the DNA translocase motor to drive efficient DNA fork regression. J Biol Chem 293:8484-8494
Wang, Jing L; Duboc, Camille; Wu, Qian et al. (2018) Dissection of DNA double-strand-break repair using novel single-molecule forceps. Nat Struct Mol Biol 25:482-487
Crickard, J Brooks; Kaniecki, Kyle; Kwon, Youngho et al. (2018) Meiosis-specific recombinase Dmc1 is a potent inhibitor of the Srs2 antirecombinase. Proc Natl Acad Sci U S A 115:E10041-E10048
Syed, Aleem; Tainer, John A (2018) The MRE11-RAD50-NBS1 Complex Conducts the Orchestration of Damage Signaling and Outcomes to Stress in DNA Replication and Repair. Annu Rev Biochem 87:263-294
Howes, Timothy R L; Sallmyr, Annahita; Brooks, Rhys et al. (2018) Erratum to ""Structure-activity relationships among DNA ligase inhibitors; characterization of a selective uncompetitive DNA ligase I inhibitor"" [DNA Repair 60C (2017) 29-39]. DNA Repair (Amst) 61:99
Bhattacharyya, Sudipta; Soniat, Michael M; Walker, David et al. (2018) Phage Mu Gam protein promotes NHEJ in concert with Escherichia coli ligase. Proc Natl Acad Sci U S A 115:E11614-E11622
Tsai, Chi-Lin; Tainer, John A (2018) Robust Production, Crystallization, Structure Determination, and Analysis of [Fe-S] Proteins: Uncovering Control of Electron Shuttling and Gating in the Respiratory Metabolism of Molybdopterin Guanine Dinucleotide Enzymes. Methods Enzymol 599:157-196
Ogorzalek, Tadeusz L; Hura, Greg L; Belsom, Adam et al. (2018) Small angle X-ray scattering and cross-linking for data assisted protein structure prediction in CASP 12 with prospects for improved accuracy. Proteins 86 Suppl 1:202-214

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