Dr. Joann Sweasy

Professor

Maintenance of Genome Stability

Oxidative DNA damage occurs at a rate of about 20,000 lesions per cell per day. The base excision repair (BER) system repairs this DNA damage and therefore maintains genome stability. BER may be a tumor suppressor mechanism. The research in my lab is focused on the functional characterization of mutants encoding variant BER enzymes and their roles in cancer and other diseases. We study germline Single Nucleotide Polymorphisms (SNPs) and mutants that arise in tumors. Our research has shown that both tumor-associated variants and germline variants of BER induce cellular transformation in immortal cells in culture. The molecular mechanism of transformation results from genomic instability.

Our laboratory also focuses on the function of variants of other DNA repair processes including homology directed repair. Deficiencies in this process also lead to genomic instability and we are working on characterizing the contribution of specific variants to this process.

Meiosis relies on several DNA repair enzymes and we have focused our efforts on the roles of DNA polymerase beta (Pol beta) in this process. We have shown that proper function of Pol beta is critical for Prophase I of meiosis and are now studying the roles of Pol beta and its interacting proteins in meiosis, using a combined genetic and biochemical approach.

The biochemical functions of DNA repair variants identified in the germline and in tumors are important for understanding their aberrant functions in cells. Our laboratory uses a combination of enzymology and fluorescence based assays to study these DNA repair variants in order to elucidate their roles in cancer and other diseases.

BACKGROUND

Dr. Sweasy received her Ph.D. at Rutgers University under the direction of Evelyn M. Witkin. She did postdoctoral research with Lawrence A. Loeb at the University of Washington where she initiated her research into mechanisms of genomic instability induced by mutant DNA polymerases.

LAB MEMBERS

Heather Galick
        Senior Research Technician

SELECTED PUBLICATIONS

Senejani AG, Dalal S, Liu Y, Nottoli TP, McGrath JM, Clairmont CS, Sweasy JB. Y265C DNA polymerase beta knockin mice survive past birth and accumulate base excision repair intermediate substrates. Proc Natl Acad Sci U S A. 2012 Apr 24;109(17):6632-7.

Murphy DL, Jaeger J, Sweasy JB. A triad interaction in the fingers subdomain of DNA polymerase beta controls polymerase activity. J Am Chem Soc. 2011 Apr 27;133(16):6279-87.

Kidane D, Jonason AS, Gorton TS, Mihaylov I, Pan J, Keeney S, de Rooij DG, Ashley T, Keh A, Liu Y, Banerjee U, Zelterman D, Sweasy JB. DNA polymerase beta is critical for mouse meiotic synapsis. EMBO J. 2010 Jan 20;29(2):410-23.

Lang T, Dalal S, Chikova A, DiMaio D, Sweasy JB. The E295K DNA polymerase beta gastric cancer-associated variant interferes with base excision repair and induces cellular transformation. Mol Cell Biol. 2007 Aug;27(15):5587-96.

Sweasy JB, Lang T, Starcevic D, Sun KW, Lai CC, Dimaio D, Dalal S. Expression of DNA polymerase {beta} cancer-associated variants in mouse cells results in cellular transformation. Proc Natl Acad Sci U S A. 2005 Oct 4;102(40):14350-5.