Faculty Articles

Title

DNA damage-processing pathways involved in the eukaryotic cellular response to anticancer DNA cross-linking drugs.

ISBN or ISSN

0026-895X

Publication Title

Molecular pharmacology

Volume

65

Issue

6

Publication Date / Copyright Date

6-1-2004

First Page

1496

Last Page

1506

Publisher

American Society for Pharmacology and Experimental Therapeutics

DOI Number

10.1124/mol.65.6.1496

Abstract

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.

Disciplines

Medical Specialties | Medicine and Health Sciences | Osteopathic Medicine and Osteopathy

Keywords

Antineoplastic Agents, Base Pair Mismatch, Carmustine, Cell Cycle, Cisplatin, Cross-Linking Reagents, DNA, DNA Adducts, DNA Damage, DNA Repair, Mitomycin, Mutation, Nitrogen Mustard Compounds, Yeasts

Peer Reviewed

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