OF WORK: Understanding the relationships between structure and function for a DNA enzyme holds the promise of allowing us to develop specific inhibitors and other modulators of the enzyme's activity through rational design approaches. Although this idea is now fundamental in the field of structural biology, we are still in the earliest stages of bringing the approach to its full potential. Our studies of mammalian DNA polymerase beta have pioneered in the use of a coordinated approach of structural studies (x-ray crystallography, NMR, and spectroscopy), biochemical studies and mammalian genetic studies. This approach has allowed us to establish the cellular role of DNA polymerase beta in mammalian base excision repair. And, the approach has allowed us to establish a solid framework for future studies of the role of individual amino acid residues in this enzyme in such important endpoints as the speed of DNA repair, coordination of DNA synthesis with DNA ligation, coordination of dRPase with DNA synthesis, the fidelity of DNA synthesis, the fidelity of overall DNA base excision repair, and lesion bypass. Rational drug design targeting these endpoints will allow us to strategically regulate base excision repair with DNA polymerase beta specific drugs. Detailed structure-function relationship studies of other base excision repair enzymes, such as 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 de-regulate base excision repair in cells. This could have implications for chemotherapy and for understanding the role of DNA repair in preventing disease especially after exposure to environmental toxins.
| 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 |
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