Epigenetic mechanisms of drug resistance: drug-induced DNA hypermethylation and drug resistance.

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dc.contributor.authorNyce, Jonathan W.en_US
dc.contributor.authorLeonard, Sherry Annen_US
dc.contributor.authorCanupp, Dawnen_US
dc.contributor.authorSchulz, Stefanen_US
dc.contributor.authorWong, Soen_US
dc.date.accessioned2011-04-15T19:24:42Zen_US
dc.date.accessioned2011-05-17T00:33:30Z
dc.date.available2011-04-15T19:24:42Zen_US
dc.date.available2011-05-17T00:33:30Z
dc.date.issued1993-04-01en_US
dc.description.abstractIn a model system employing Chinese hamster V-79 cells, the DNA synthesis inhibitor 3'-azido-3'- deoxythymidine (BW A509U, AZT) was shown to induce genome-wide DNA hypermethylation, low-frequency silencing of thymidine kinase (TK; EC 2.7.1.21) gene expression, and resistance to AZT. Twenty-four hours of exposure of V-79 cells to 150 ,uM AZT led to >2-fold enhancement of genomic 5-methylcytosine levels and produced TK- epimutants at a rate -43-fold above background. Such AZT-induced TK- epimutants were shown to be severely reduced in their capacity to activate AZT to its proximate antiviral form, AZT 5'- monophosphate, as compared with the TK+ parental cell line from which they were derived. TK- clones isolated under these conditions were shown to be 9- to 24-fold more resistant to the cytotoxic effects of AZT than the parental TK+ cell line and showed collateral resistance to 5-fluoro-2'-deoxyuridine. Three of four TK- epimutants could be reactivated at very high frequency (8-73%) to the TK+ AZT-sensitive phenotype by 24 hr of exposure to the demethylating agent 5-azadeoxycytidine (5-azadC), implying that drug-induced DNA hypermethylation, rather than classical mutation, was involved in the original gene-silencing event in these three clones. These 5-azadC-induced TK+ revertants concomitantly regained the ability to metabolize AZT to its 5'-monophosphate. RNA slot blot analyses indicated that the four AZT-induced TK- clones expressed 8.9%, 15.6%, 17.8%, and 11.1% of the parental level ofTK mRNA. The three clones that were reactivatable by 5-azadC showed reexpression of TK mRNA to levels 84.4%, 51.1%, and 80.0% that of the TK+ parental cell line. These experiments show that one potential mechanism of drug resistance involves drug-induced DNA hypermethylation and resulting transcriptional inactivation of cellular genes whose products are required for drug activation. Originally published Proceedings of the National Academy of Science, Vol. 90, No. 7, Apr 1993en_US
dc.identifier.citationProceedings of the National Academy of Sciences; 90:7 p. 2960-2964en_US
dc.identifier.doi10.1073/pnas.90.7.2960
dc.identifier.pmidPMC46216en_US
dc.identifier.urihttp://hdl.handle.net/10342/3366en_US
dc.language.isoen_USen_US
dc.publisherEast Carolina Universityen_US
dc.relation.urihttp://www.pnas.org/content/by/year/1993en_US
dc.rightsAuthor notified of opt-out rights by Cammie Jennings prior to upload of this article.en_US
dc.subjectDNA methylationen_US
dc.subjectEpimutantsen_US
dc.subject3'-azido-3'-deoxythymidineen_US
dc.subject5-fluoro-2'-deoxyuridineen_US
dc.subjectGene silencingen_US
dc.titleEpigenetic mechanisms of drug resistance: drug-induced DNA hypermethylation and drug resistance.en_US
dc.typeArticleen_US
ecu.journal.issue7
ecu.journal.nameProceedings of the National Academy of Sciences
ecu.journal.pages2960-2964
ecu.journal.volume90

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