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Disparity between DNA Base Excision Repair in Yeast and Mammals

Translational Implications¹

Department of Pediatrics, Section of Hematology/Oncology, Herman B. Wells Center for Pediatric Research, and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202 [M. R. K.]; Department of Radiation Oncology, Emory University School of Medicine, Atlanta, Georgia 30303 [Y. W. K.]; and Laboratory of Molecular Gerontology, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224 [D. M. W.]

ABSTRACT

One approach to the effective treatment of cancer requires the continued development of novel chemotherapeutic agents to kill tumor cells. Additionally, an element of cancer research has been devoted to understanding DNA repair pathways in hopes of defining the factors that confer resistance to anticancer drugs and developing strategies for modulating repair capacity as a means of overcoming resistance or enhancing sensitivity to cancer treatments. Historically, yeast, particularly Saccharomyces cerevisiae, has been used as a model system for DNA repair analyses. Additionally, it has been used to evaluate drug efficacy and selectivity, and to identify new targets for antitumor drugs. The usefulness of yeast for these types of analyses has been primarily because of it being considered to have well-conserved DNA repair processes among eukaryotes. However, as more information has accumulated in mammalian DNA repair, and particularly in DNA base excision repair (BER), a number of striking differences have emerged between yeast and mammalian (human) repair processes. The BER pathway is essential for the repair of damaged DNA induced by oxidizing and alkylating agents, which are the majority of chemotherapeutic drugs used currently in the clinic. The importance of this pathway in processing DNA damage makes its members potential targets for novel chemotherapeutic agents. However, because the BER process and its main players are remarkably divergent from S. cerevisiae to humans, it is worth keeping these differences in mind if yeast continues to be used as a model or primary system in the screening for potential new human therapeutics.

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