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) homologous recombinational repair, and
5) mismatch repair.
The resulting biologically driven determinations of repair protein structures will apply the comparative knowledge of the sequenced bacterial, archaeal, 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 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 cooperativity 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 design of epidemiological studies and will provide the logical next step to fully utilizing the information on individual polymorphisms in DNA repair proteins being developed by the DOE and NIH Environmental and Human Genome Project.
| Name | Organization | Role on Project |
|---|---|---|
| Tainer, John A. | UC / Lawrence Berkeley National Laboratory | Principal Investigator; Project 3 Leader; SCB Core Director and ADM Core co-Director |
| Cooper, Priscilla K | . UC / Lawrence Berkeley National Laboratory | Co-Principal Investigator; Project 2 Leader; ADM and EMB Core Director |
| Beese, Lorena S. | Duke University Medical School | Project 5 Senior Investigator; SCB Core co-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 |
| Earnest, Thomas N. | UC / Lawrence Berkeley National Laboratory | SCB Core Investigator |
| Ellenberger, Thomas | Harvard Medical School | Project 1 Senior Investigator; EMB and SCB Core co-Director |
| Genick, Ulrich | UC / Lawrence Berkeley National Laboratory | Lead Research Scientist, SCB Core |
| Kolodner, Richard D. | UC San Diego School of Medicine | Project 5 Senior Investigator |
| Kowalczykowski, Stephen | Univ. of California at Davis | Project 4 Senior Investigator |
| Matsumoto, Yoshihiro | Fox Chase Cancer Center | Project 2 Senior Investigator |
| Mitra, Sankar | University of Texas Medical Branch | Project 2 Senior Investigator |
| Modrich, Paul L. | Duke University Medical School | Project 5 Leader |
| Nogales, Eva | UC / Lawrence Berkeley National Laboratory | Project 2 Senior Investigator |
| Qin, Jun | Baylor University | Project 3 Senior Investigator |
| Samson, Leona | Harvard School of Public Health | Project 1 Leader |
| Schild, David | UC / Lawrence Berkeley National Laboratory | Project 4 Senior Investigator |
| Thompson, Larry | Lawrence Livermore National Laboratory | Project 4 Leader |
| Tomkinson, Alan | University of Texas Health Science Center | Project 1 Senior Investigator |
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 Fox Chase Cancer Center 7701 Burholme Avenue Philadelphia, PA 19111 Harvard School of Public Health Department of Cancer Cell Biology Division of Toxicology 665 Huntington Avenue, I-607B Boston, MA 02115 Duke University Medical School Department of Biochemistry Box 3711 Duke Medical Center Durham, NC 27710 Harvard Medical School Department BCMP 240 Longwood Avenue Boston, MA 02115 Lawrence Livermore National Laboratory BBR Program L452 P.O. Box 808 Livermore, CA 94551 U.C. San Diego School of Medicine Ludwig Institute for Cancer Research CMME-3080 9500 Gilman Drive La Jolla, CA 92093 University of Maryland School of Medicine Radiation Oncology Research Laboratory Bressler Research Building, 6-015 655 West Baltimore Street Baltimore, MD 21201 University of Texas Medical Branch Sealy Center for Molecular Science and Dept. of Human Biological Chemistry 6.136 Medical Research Building Galveston, TX 77555-1079 Univ. of California at Davis Department of Microbiology and Molecular & Cellular Biology Hutchison Hall Room 258 Davis, CA 95616-8665 University of Texas Health Science Center Institute of Biotechnology, Department of Molecular Medicine 15355 Lambda Drive San Antonio, TX 78245
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