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Professor of BiochemistryProfessor of
Primary Office: 4-610 BSBIowa City, IA 52242
Email: email@example.comWeb: Washington Laboratory
BA, Philosophy, The Ohio State UniversityBS, Biology, The Ohio State UniversityPhD, Biochemistry, The Ohio State University
Post Doctorate, University of Texas Medical Branch at Galveston
Department of Biochemistry PhDInterdisciplinary Graduate Program in Molecular and Cellular BiologyInterdisciplinary Graduate Program in Translational BiomedicineMedical Scientist Training Program
Classical, replicative DNA polymerases synthesize DNA in a template-dependent fashion with remarkable efficiency and fidelity. They achieve rates as high as 1,000 nucleotide incorporations per second with error frequencies as low as one error per one million nucleotides incorporated. What these amazing enzymes cannot do, however, is replicate through DNA lesions that arise spontaneously or are formed upon attack by a plethora of DNA damaging agents including oxygen free radicals and radiation. Consequently, organisms have evolved specialized polymerases to replicate through lesions. DNA polymerase eta is one such specialized polymerase. Inactivation of DNA polymerase eta in yeast leads to an increase in the frequency of ultraviolet (UV) radiation-induced mutations. This indicates that the replication of UV- induced lesions by this polymerase is error-free ( i.e. , not mutagenic). In vitro , DNA polymerase eta has the unprecedented ability to accurately replicate through a thymine dimer, a common UV-induced lesion. Furthermore, defects in human DNA polymerase eta are responsible for the cancer prone genetic disorder, the variant form of xeroderma pigmentosum. DNA polymerase zeta is another specialized polymerase. Inactivation of DNA polymerase zeta in yeast leads to a dramatic decrease in the frequency of mutations induced by a wide range of DNA damaging agents. This indicates that the replication of numerous lesions by this polymerase is mutagenic. In vitro , DNA polymerase zeta has the remarkable ability to efficiently extend from primer- terminal mismatches containing template lesions. Thus, DNA polymerase zeta likely functions in the mutagenic replication of damaged DNA by extending from nucleotides inserted opposite lesions by other polymerases?often the classical, replicative polymerases themselves. Our long- term goal is to understand the mechanisms of DNA polymerases involved in both mutagenic and error-free replication of DNA damage at the thermodynamic, kinetic, and structural level. We use a variety of approaches including equilibrium binding techniques, transient state kinetic analyses (both rapid chemical quench flow and fluorescence-based stopped flow methods), and the characterization of mutant proteins generated by site-directed mutagenesis. We hope that this work will contribute to our understanding of the origins of mutations and cancers and perhaps gain new insights into their prevention.
Holden Comprehensive Cancer Center
Dead-End Elimination with a Polarizable Force Field Repacks PCNA Structures..
2015 August 18. 109(4):816-26.
Structurally distinct ubiquitin- and sumo-modified PCNA: implications for their distinct roles in the DNA damage response..
Structure (London, England : 1993).
2015 April 7. 23(4):724-33.
Eukaryotic Y-Family Polymerases: A Biochemical and Structural Perspective.
Nucleic Acid Polymerases: Nucleic Acids and Molecular Biology.
Distinct structural alterations in PCNA block DNA mismatch repair.
2013 July. Epub ahead of print.
PCNA trimer instability inhibits translesion synthesis by DNA polymerase Î· and by DNA polymerase Î´.
2013 May. 12(5):367-76.
Structure and functional analysis of the BRCT domain of translesion synthesis DNA polymerase Rev1.
2013 January. 52(1):254-63.
Pre-steady state kinetic studies show that an abasic site is a cognate lesion for the yeast Rev1 protein.
2011 November. 10(11):1138-44.
Crystal structure of SUMO-modified proliferating cell nuclear antigen.
Journal of molecular biology.
2011 February. 406(1):9-17.
Variations on a theme: eukaryotic Y-family DNA polymerases.
Biochimica et biophysica acta.
2010 May. 1804(5):1113-23.
Structure of monoubiquitinated PCNA and implications for translesion synthesis and DNA polymerase exchange.
Nature structural & molecular biology.
2010 April. 17(4):479-84.
Date Last Modified: 06/06/2016 -
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