This year our group, often in collaboration with others, published six studies related to DNA replication fidelity. The first four investigated the origins of ribonucleotides in DNA, their repair, and their consequences. (1) We showed the exonuclease activity of yeast and human Pol delta are largely unable to proofread newly inserted ribonucleotides. (2) We discovered that in the absence of RNase H2-dependent repair of ribonucleotides present in DNA, a second type of ribonucleotide repair is initiated by topoisomerase 1. (3) In collaboration with R. Scott Williams, we showed that aprataxin resolves adenylated RNA-DNA junctions to maintain genome integrity. (4) 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 Marc Greenberg to investigate DNA polymerase lambda inactivation by oxidized abasic sites, and collaborated with Patricia Opresko to show that DNA polymerase stalls on telomeric lagging strand templates independently from G-quadruplex formation.

Project Start
Project End
Budget Start
Budget End
Support Year
23
Fiscal Year
2013
Total Cost
$1,022,177
Indirect Cost
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State
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Zip Code
Burgers, Peter M J; Kunkel, Thomas A (2017) Eukaryotic DNA Replication Fork. Annu Rev Biochem 86:417-438
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
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:
Burgers, Peter M J; Gordenin, Dmitry; Kunkel, Thomas A (2016) Who Is Leading the Replication Fork, Pol ? or Pol ?? Mol Cell 61:492-493
Williams, Jessica S; Lujan, Scott A; Kunkel, Thomas A (2016) Processing ribonucleotides incorporated during eukaryotic DNA replication. Nat Rev Mol Cell Biol 17:350-63
Watt, Danielle L; Buckland, Robert J; Lujan, Scott A et al. (2016) Genome-wide analysis of the specificity and mechanisms of replication infidelity driven by imbalanced dNTP pools. Nucleic Acids Res 44:1669-80
Lujan, Scott A; Williams, Jessica S; Kunkel, Thomas A (2016) DNA Polymerases Divide the Labor of Genome Replication. Trends Cell Biol 26:640-54
Lujan, Scott A; Williams, Jessica S; Kunkel, Thomas A (2016) Eukaryotic genome instability in light of asymmetric DNA replication. Crit Rev Biochem Mol Biol 51:43-52
Conover, Hailey N; Lujan, Scott A; Chapman, Mary J et al. (2015) Stimulation of Chromosomal Rearrangements by Ribonucleotides. Genetics 201:951-61

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