Atypical multidrug resistance may be associated with catalytically active mutants of human DNA topoisomerase II α

Yoshito Okada, Aki Tosaka, Yuji Nimura, Akihiko Kikuchi, Shonen Yoshida, Motoshi Suzuki

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15 Citations (Scopus)

Abstract

In human cells, atypical drug resistance was previously identified with reduced catalytic activity or nuclear localization efficiency of DNA topoisomerase IIα (TOP2α). We have shown two etoposide resistant hTOP2α mutants, K798L and K798P confer resistance to etoposide. In this work, we showed these mutants are also resistant against doxorubicin and mAMSA in vivo in the yeast strain ISE2, rad52, top2-4 at the non-permissive temperature. We purified these mutants to characterize the drug resistant mechanism. Purified recombinant proteins were 8- to 12-fold more resistant to etoposide and doxorubicin than wild type TOP2α, and 2-fold more resistant to amsacrine, as measured by accumulation of cleavable DNA. These data show that K798L and K798P may be intrinsically resistant against these drugs in vitro and that this character may confer atypical multidrug resistant phenotype in vivo in yeast.

Original languageEnglish
Pages (from-to)141-148
Number of pages8
JournalGene
Volume272
Issue number1-2
DOIs
Publication statusPublished - 11-07-2001
Externally publishedYes

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All Science Journal Classification (ASJC) codes

  • Genetics

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