Professor of Therapeutic Radiology and Genetics and Cancer Genetics Program

* B.A. Beaver College, 1980
* Ph.D. Rutgers, The State University of New Jersey, 1989

Research Interests:

* Genome Stability
* Mutagenesis
* DNA Replication
* DNA Repair
* Carcinogenesis

Other interests:

* Association for Women in Science

Honors:

* Argall and Anna Hull Award
* American Cancer Society Junior Faculty Research Award
* Donaghue Investigator Award

Current Research:

The focus of my research is genomic instability and how it leads to the mutations that result in human diseases such as cancer. The goal of one of the projects in my laboratory is to understand how DNA polymerases synthesize DNA accurately, and how they make mistakes that result in mutations. We study DNA mammalian DNA polymerase beta (Pol ß) because it was a relatively small, single subunit enzyme that could be easily manipulated and purified. My laboratory developed a method for assessing the activity and accuracy of rat Pol ß in bacteria. This led to the identification of a number of variants of Pol ß that synthesized DNA inaccurately. Our focus upon detailed biochemical characterization of variants of the Pol ß protein has shown that single amino acid residues that are quite distant from the active site of the enzyme are very important for accurate DNA synthesis. We found that many of these residues act at a distance in DNA positioning, nucleotide binding, and by influencing the rates of conformational changes that are important for accurate DNA synthesis. A second project is focused upon tumor-associated variants of Pol ß. Pol ß functions in base excision repair. The base excision repair system is responsible for removal of at least 10,000 DNA lesions per day. Interestingly, the Pol ß gene appears to be mutated in a large percentage of tumors. We have found that expression of the tumor-associated variants in mouse cells results in cellular transformation that has a mutational mechanism. We have shown that some of the Pol ß variants synthesize DNA inaccurately and others have no catalytic activity, but can bind to DNA and interfere with its repair. Our results suggest that the variants compromise base excision repair and lead to the induction of mutations, and suggest that base excision repair itself is a tumor suppressor mechanism. These studies impact our fundamental understanding of DNA repair and have the potential to lead to the design of targeted cancer therapeutics.