Gene-specific DNA repair of interstrand cross-links induced by chemotherapeutic agents can be preferential.
The gene-specific formation and repair of interstrand cross-links (ICL) were measured in the dihydrofolate reductase (DHFR) gene in hamster cells. Cells were treated with two different chemotherapeutic agents, nitrogen mustard and cisplatin, and the frequency of cross-links was quantified in the active gene and in a downstream, inactive region. About 5% of total lesions induced by these agents were ICL. Whereas the frequencies of cross-links formed were similar in the gene and in the noncoding region after cisplatin treatment, there were more nitrogen mustard-induced cross-links in the inactive region than in the active gene. At low levels of cross-linking, we found preferential DNA repair in the active gene as compared to the inactive region. At higher levels of cross-linking, there was no difference in repair rates between the gene and the noncoding region due to an increase in the repair efficiency in the inactive DNA. Implications of fine structural organization of cross-link repair are discussed.
Larminat
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F
Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Zhen
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W
Bohr
V A
VA
D000818:Animals; D016466:CHO Cells; D002945:Cisplatin / Q000737:chemistry / Q000633:toxicity*; D006224:Cricetinae; D003432:Cross-Linking Reagents / Q000737:chemistry*; D004247:DNA / Q000737:chemistry; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication; D005796:Genes; D066298:In Vitro Techniques; D008466:Mechlorethamine / Q000737:chemistry / Q000633:toxicity*; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics; D014158:Transcription, Genetic
D003432:Cross-Linking Reagents; D008466:Mechlorethamine; D004247:DNA; D013762:Tetrahydrofolate Dehydrogenase; D002945:Cisplatin