Cancer predispositions result from defects in DNA damage responses. This integrated multi-institutional Program Project on the Structural Cell Biology of DNA Repair Machines (SBDR) addresses the challenge of characterizing these critical DNA damage responses at the molecular level. Our SBDR renewal application integrates projects that investigate the structural biology and pathway interactions for DNA damage responses key to genetic integrity. The interconnected SBDR projects are: 1) Nucleotide and base excision repair, 2) Transcription-coupled and replication-associated excision repair; 3. Homologous recombination and crosslink repair, and 4) Mismatch repair interactions. Together SBDR projects focus on protein conformations, interactions, and complexes that are keystones for understanding and ultimately controlling DNA damage responses for therapeutic purposes. As a whole, SBDR addresses four unifying hypotheses for DNA damage response proteins: 1) their interactions form super-efficient molecular machines to detect, repair, and signal damage, 2) their interactions are structurally regulated by post-translational modifications (PTMs), conformational switching, and disorder-order transitions induced by protein and DNA binding; 3) their dynamic assemblies result from linking weak modular interactions to achieve overall high affinities and binding specificities, and 4) their pathway choices and steps are selectively regulated by composite modular interactions that allow interface mimicry, invasion, and DNA damage specific exchanges. SBDR will test hypotheses and achieve program goals by integrating existing strengths with new technologies and strategic collaborations. The Structural Cell Biology (SCB) Core will leverage the successes of the SIBYLS beamline for visualizing protein assemblies and conformations by coupled solution and crystallographic X-ray diffraction analyses, and will add the complementary method of Scanning Force Microscopy. The Administrative Core will continue to manage the SBDR, monitor progress, and facilitate interaction among all investigators. The combined Project and Core efforts will allow SBDR to effectively bridge from protein interactions to pathways, from repair pathway interactions to damage sensing, signaling, and repair responses, and from damage response interactions to cell fate decisions and phenotypes. The application of SBDR results to both understanding and intervention for cancer will be promoted by active interactions with the UCSF Cancer Center. Overall, SBDR results will be fundamental to informed design of epidemiological studies and provide the next step moving from systems biology toward achieving a molecular-based understanding for cancer risk, prevention and treatment. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA092584-06
Application #
7138809
Study Section
Subcommittee G - Education (NCI)
Program Officer
Pelroy, Richard
Project Start
2001-09-27
Project End
2011-08-31
Budget Start
2006-09-26
Budget End
2007-08-31
Support Year
6
Fiscal Year
2006
Total Cost
$3,300,000
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
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
Langelier, Marie-France; Zandarashvili, Levani; Aguiar, Pedro M et al. (2018) NAD+ analog reveals PARP-1 substrate-blocking mechanism and allosteric communication from catalytic center to DNA-binding domains. Nat Commun 9:844
Crickard, J Brooks; Greene, Eric C (2018) Biochemical attributes of mitotic and meiotic presynaptic complexes. DNA Repair (Amst) :

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