This year our group, often in collaboration with others, published six primary studies related to DNA replication fidelity. We showed that DNA polymerase delta stalls when replicating telomeric DNA sequences. Surprisingly compared to expectations from the current literature, this stalling occurs independent of formation of G-quadruplexes in DNA. In collaboration with R. Scott Williams group, we showed that aprataxin resolves adenylated RNA-DNA junctions to maintain genome integrity. In collaboration with L.C. Pedersen, we performed a structure-function analysis of ribonucleotide bypass by B family DNA replicases. We also continued to collaborate with Dr. Pedersen, and added a new collaboration with M. Garcia-Diaz, to perform three novel structure-function studies of Family X DNA polymerases lambda and mu that participate in repairing DNA damage resulting from physical and chemical environmental stressors. In addition, we published a methodology article, two review articles and an article highlighting a major breakthrough in DNA replication enzymology.

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Budget End
Support Year
24
Fiscal Year
2014
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Indirect Cost
Name
U.S. National Inst of Environ Hlth Scis
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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

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