Abstract

This year, we published the following accomplishments. (1) We characterized a mutator derivative of yeast DNA polymerase zeta, which has a critical role in determining the rate of both spontaneous and DNA damage-induced mutagenesis in eukaryotes. (2) In collaboration with the computational group in LSB, we investigated the mechanism of catalysis by human DNA polymerase lambda. (3) We demonstrated that during gap filling DNA repair synthesis, DNA polymerase lambda scrunches the yet-to-be-copied template base in a binding pocket comprised of three conserved amino acids. (4) We investigated the roles of DNA polymerases delta and eta in translesion DNA synthesis of 8-oxo-guanine, one of the most common and mutagenic lesions resulting from oxidative stress. (5) We published comprehensive reviews on the roles of the major replicative DNA polymerases in leading strand and lagging strand DNA synthesis, and on mechanisms by which high fidelity DNA replication is achieved. In addition, we made substantial, but as yet unpublished, progress on the several other aspects of DNA replication and polymerase functions.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAES065070-19
Application #
7968082
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
19
Fiscal Year
2009
Total Cost
$2,289,672
Indirect Cost

  Institution

Name
National Institute of Environmental Health Sciences
Department
Type
DUNS #
City
State
Country
Zip Code

  Publications

Williams, Jessica S; Kunkel, Thomas A (2018) Studying Topoisomerase 1-Mediated Damage at Genomic Ribonucleotides. Methods Mol Biol 1703:241-257
Kaminski, Andrea M; Tumbale, Percy P; Schellenberg, Matthew J et al. (2018) Structures of DNA-bound human ligase IV catalytic core reveal insights into substrate binding and catalysis. Nat Commun 9:2642
Zhou, Zhi-Xiong; Williams, Jessica S; Kunkel, Thomas A (2018) Studying Ribonucleotide Incorporation: Strand-specific Detection of Ribonucleotides in the Yeast Genome and Measuring Ribonucleotide-induced Mutagenesis. J Vis Exp :
Kunkel, Thomas A (2018) A simple but profound mutation in mouse DNA polymerase ? drives tumorigenesis. J Clin Invest :
Huang, Shar-Yin N; Williams, Jessica S; Arana, Mercedes E et al. (2017) Topoisomerase I-mediated cleavage at unrepaired ribonucleotides generates DNA double-strand breaks. EMBO J 36:361-373
Kunkel, Thomas A; Burgers, Peter M J (2017) Arranging eukaryotic nuclear DNA polymerases for replication: Specific interactions with accessory proteins arrange Pols ?, ?, and ? in the replisome for leading-strand and lagging-strand DNA replication. Bioessays 39:
Williams, Jessica S; Gehle, Daniel B; Kunkel, Thomas A (2017) The role of RNase H2 in processing ribonucleotides incorporated during DNA replication. DNA Repair (Amst) 53:52-58
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
Burgers, Peter M J; Kunkel, Thomas A (2017) Eukaryotic DNA Replication Fork. Annu Rev Biochem 86:417-438
Burgers, Peter M J; Gordenin, Dmitry; Kunkel, Thomas A (2016) Who Is Leading the Replication Fork, Pol ? or Pol ?? Mol Cell 61:492-493

Showing the most recent 10 out of 72 publications