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DNA Damage-Processing Pathways Involved in the Eukaryotic Cellular Response to Anticancer DNA Cross-Linking Drugs

Departments of Chemistry (V.B., L.G.M.) and Biochemistry (P.W.D.) and Division of Cancer Biology and Department of Radiation Oncology (P.W.D.), Emory University, Atlanta, Georgia; and Department of Chemistry, Louisiana State University, Baton Rouge, Louisiana (L.G.M.)

We used a panel of isogenic Saccharomyces cerevisiae strains compromised in several different DNA damage-processing pathways to assess in vivo processing of DNA adducts induced by four cross-linking anticancer drugs. By examining cytotoxicity profiles, cell cycle arrest patterns, and determining recombination and mutation frequencies, we found that cisplatin-, nitrogen mustard-, mitomycin-, and carmustine-induced DNA adducts in S. cerevisiae are processed by components of the nucleotide excision repair (NER), recombination repair (RR), and translesion synthesis (TLS) pathways, with substantially different contributions of each pathway for the drugs studied here. In contrast to previous studies that used single pathway-compromised strains to identify genes that mediate sensitivity to DNA cross-linking drugs, we used strains that were compromised in multiple pathways. By doing so, we were able to establish several functions that were previously unknown and interconnections between different DNA damage-processing pathways. To our surprise, we found that for cisplatin-induced cytotoxicity, TLS and RR contribute to survival to a significant extent. In the case of nitrogen mustard DNA adduct processing, equal involvement of two major pathways was established: one that requires functional RR and NER components and one that requires functional TLS and NER components. These data reveal the complexity of DNA cross-link processing that, in many cases, requires interactions of components from several different DNA damage-processing systems. We demonstrate the usefulness of yeast strains with multiple simultaneous defects in DNA damage-processing pathways for studying the modes of action of anticancer drugs.

Address correspondence to: Paul W. Doetsch, Department of Biochemistry, Emory University School of Medicine, 1510 Clifton Road, Atlanta, GA 30322. E-mail: medpwd{at}emory.edu

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