of Work: Rare replication errors are corrected by the cell?s spellchecking machinery, post-replication DNA mismatch repair (MMR). The goal of this project is to understand the biochemistry and genetics of MMR in normal and mutant eukaryotic cells. This year, in conjunction with our collaborators, we have: i) provided evidence to support the hypothesis that sporadic colon cancer is linked to epigenetic inactivation of mismatch resulting from loss of expression of hMLH1 due to promoter hypermethylation, ii) established that 100% of MSH6 knockout mice get cancer, iii) demonstrated an effect of PMS2 on somatic hypermutagenesis of immunoglobulin genes, iv) demonstrated complementation of a MMR defect in a human tumor cell line by introducing only the hPMS2 gene, v) described the overlapping heteroduplex substrate specificities of the two known mismatch repair recognition complexes, hMutSalpha and hMutSbeta, vi) established a link between defective MMR genes and resistance to cisplatin, vii) provided evidence against a role for the Werner Syndrome helicase/exonuclease in MMR, and viii) provided evidence that MMR influences base analogue-induced mutagenesis. These studies are important for understanding the genetics and biochemistry of the mismatch repair system, the multiple functions of the numerous mismatch repair genes, the molecular genetic basis for the initiating events in cancer and its subsequent treatment and the risk posed to individuals in the population by exposure to DNA damaging agents.
| Burgers, Peter M J; Kunkel, Thomas A (2017) Eukaryotic DNA Replication Fork. Annu Rev Biochem 86:417-438 |
| 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 |
| Makarova, Alena V; Nick McElhinny, Stephanie A; Watts, Brian E et al. (2014) Ribonucleotide incorporation by yeast DNA polymerase ?. DNA Repair (Amst) 18:63-7 |
| Schaetzlein, Sonja; Chahwan, Richard; Avdievich, Elena et al. (2013) Mammalian Exo1 encodes both structural and catalytic functions that play distinct roles in essential biological processes. Proc Natl Acad Sci U S A 110:E2470-9 |
| Sparks, Justin L; Chon, Hyongi; Cerritelli, Susana M et al. (2012) RNase H2-initiated ribonucleotide excision repair. Mol Cell 47:980-6 |
| Lujan, Scott A; Williams, Jessica S; Pursell, Zachary F et al. (2012) Mismatch repair balances leading and lagging strand DNA replication fidelity. PLoS Genet 8:e1003016 |
| Kunkel, Thomas A (2011) Balancing eukaryotic replication asymmetry with replication fidelity. Curr Opin Chem Biol 15:620-6 |
| Jirawatnotai, Siwanon; Hu, Yiduo; Michowski, Wojciech et al. (2011) A function for cyclin D1 in DNA repair uncovered by protein interactome analyses in human cancers. Nature 474:230-4 |
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