This year, we published a comprehensive SnapShot of DNA mismatch repair that is intended to be a brief, up-to-date and easy to use reference for students and for investigators in this field. We also made substantial progress in our research on the two aspects of eukaryotic DNA mismatch repair. (1) We investigated the ability of yeast Pms1, an essential mismatch repair protein, to bind to DNA. This ability is required for the essential endonuclease activity of the Mlh1-Pms1 protein complex. This investigation involved a collaboration to solve the crystal structure of the Pms1 N-terminal domain, followed by genetic and biochemical experiments to map the surface of Pms1 that interacts with DNA. (2) We participated in continuing collaborations to investigate the roles of MutS alpha and exonuclease 1 in DNA mismatch repair in mice. This included publication of the characterization of an Msh2-conditional knockout mouse model for studying intestinal cancer and for testing anticancer agents. (3) We also continued intensive (unpublished) experiments aimed at determining the efficiency with which mismatches made during leading and lagging strand DNA replication in yeast are repaired.

Project Start
Project End
Budget Start
Budget End
Support Year
14
Fiscal Year
2010
Total Cost
$761,190
Indirect Cost
City
State
Country
Zip Code
Burkholder, Adam B; Lujan, Scott A; Lavender, Christopher A et al. (2018) Muver, a computational framework for accurately calling accumulated mutations. BMC Genomics 19:345
Van, Christopher; Williams, Jessica S; Kunkel, Thomas A et al. (2015) Deposition of histone H2A.Z by the SWR-C remodeling enzyme prevents genome instability. DNA Repair (Amst) 25:9-14
Lujan, Scott A; Clark, Alan B; Kunkel, Thomas A (2015) Differences in genome-wide repeat sequence instability conferred by proofreading and mismatch repair defects. Nucleic Acids Res 43:4067-74
Kunkel, Thomas A; Erie, Dorothy A (2015) Eukaryotic Mismatch Repair in Relation to DNA Replication. Annu Rev Genet 49:291-313
St Charles, Jordan A; Liberti, Sascha E; Williams, Jessica S et al. (2015) Quantifying the contributions of base selectivity, proofreading and mismatch repair to nuclear DNA replication in Saccharomyces cerevisiae. DNA Repair (Amst) 31:41-51
Liu, Songbai; Lu, Guojun; Ali, Shafat et al. (2015) Okazaki fragment maturation involves ?-segment error editing by the mammalian FEN1/MutS? functional complex. EMBO J 34:1829-43
Lujan, Scott A; Williams, Jessica S; Clausen, Anders R et al. (2013) Ribonucleotides are signals for mismatch repair of leading-strand replication errors. Mol Cell 50:437-43
Liberti, Sascha E; Larrea, Andres A; Kunkel, Thomas A (2013) Exonuclease 1 preferentially repairs mismatches generated by DNA polymerase ?. DNA Repair (Amst) 12:92-6
Schorzman, Allison N; Perera, Lalith; Cutalo-Patterson, Jenny M et al. (2011) Modeling of the DNA-binding site of yeast Pms1 by mass spectrometry. DNA Repair (Amst) 10:454-65
Castellini, Meryl A; Buguliskis, Jeffrey S; Casta, Louis J et al. (2011) Malaria drug resistance is associated with defective DNA mismatch repair. Mol Biochem Parasitol 177:143-7

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