OF WORK: Our studies of mammalian DNA polymerase beta have pioneered the use of a coordinated approach of structural studies (x-ray crystallography, NMR, and spectroscopy), biochemical studies, and mammalian genetic studies to understand genomic stability in mammalian cells. This approach has allowed us to establish the cellular role(s) of DNA polymerase beta in mammalian base excision repair. And, the approach has allowed us to establish a solid framework for future studies of individual amino acid residues in this enzyme in such important endpoints as cellular response to genotoxicants, the rate of DNA repair, coordination of DNA repair with cellular checkpoint control and also with apoptosis signalling, coordination of deoxyribose phosphate removal (lyase activity) with DNA synthesis, the fidelity of DNA synthesis, the fidelity of overall DNA base excision repair, and DNA lesion bypass. Rational drug design, targeting one or more of these features will allow us to strategically regulate base excision repair with DNA polymerase beta specific drugs. Such agents will be useful in cancer chemotherapy and in helping us to better understand the role of DNA repair in oncogenesis and other chronic diseases. Detailed structure-function relationship studies of other base excision repair (BER) enzymes, such as FEN-1, PARP-1, XRCC1, DNA ligases I and III, AP endonuclease, and the various DNA glycosylases, will be undertaken in the future. Development of specific inhibitors or other modulators for these enzymes will allow us to strategically deregulate base excision repair in cells. This will have implications for chemotherapy and for understanding the role of DNA repair in preventing disease after exposure to environmental toxicants.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES050158-08
Application #
7007413
Study Section
(LSB)
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2004
Total Cost
Indirect Cost
Name
U.S. National Inst of Environ Hlth Scis
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Ça?layan, Melike; Wilson, Samuel H (2018) Pol ? dGTP mismatch insertion opposite T coupled with ligation reveals promutagenic DNA repair intermediate. Nat Commun 9:4213
Oertell, Keriann; Kashemirov, Boris A; Negahbani, Amirsoheil et al. (2018) Probing DNA Base-Dependent Leaving Group Kinetic Effects on the DNA Polymerase Transition State. Biochemistry 57:3925-3933
Horton, Julie K; Stefanick, Donna F; Ça?layan, Melike et al. (2018) XRCC1 phosphorylation affects aprataxin recruitment and DNA deadenylation activity. DNA Repair (Amst) 64:26-33
Horton, Julie K; Stefanick, Donna F; Zhao, Ming-Lang et al. (2017) XRCC1-mediated repair of strand breaks independent of PNKP binding. DNA Repair (Amst) 60:52-63
Prasad, Rajendra; Ça?layan, Melike; Dai, Da-Peng et al. (2017) DNA polymerase ?: A missing link of the base excision repair machinery in mammalian mitochondria. DNA Repair (Amst) 60:77-88
Howard, Michael J; Wilson, Samuel H (2017) Processive searching ability varies among members of the gap-filling DNA polymerase X family. J Biol Chem 292:17473-17481
Kirby, Thomas W; Gassman, Natalie R; Smith, Cassandra E et al. (2017) DNA polymerase ? contains a functional nuclear localization signal at its N-terminus. Nucleic Acids Res 45:1958-1970
Jamsen, Joonas A; Beard, William A; Pedersen, Lars C et al. (2017) Time-lapse crystallography snapshots of a double-strand break repair polymerase in action. Nat Commun 8:253
Perera, Lalith; Beard, William A; Pedersen, Lee G et al. (2017) Hiding in Plain Sight: The Bimetallic Magnesium Covalent Bond in Enzyme Active Sites. Inorg Chem 56:313-320
Perera, Lalith; Freudenthal, Bret D; Beard, William A et al. (2017) Revealing the role of the product metal in DNA polymerase ? catalysis. Nucleic Acids Res 45:2736-2745

Showing the most recent 10 out of 138 publications