RRC ID 32590
Author Nguyen TT, Lim JS, Tang RM, Zhang L, Chen ES.
Title Fitness profiling links topoisomerase II regulation of centromeric integrity to doxorubicin resistance in fission yeast.
Journal Sci Rep
Abstract Doxorubicin, a chemotherapeutic agent, inhibits the religation step of topoisomerase II (Top2). However, the downstream ramifications of this action are unknown. Here we performed epistasis analyses of top2 with 63 genes representing doxorubicin resistance (DXR) genes in fission yeast and revealed a subset that synergistically collaborate with Top2 to confer DXR. Our findings show that the chromatin-regulating RSC and SAGA complexes act with Top2 in a cluster that is functionally distinct from the Ino80 complex. In various DXR mutants, doxorubicin hypersensitivity was unexpectedly suppressed by a concomitant top2 mutation. Several DXR proteins showed centromeric localization, and their disruption resulted in centromeric defects and chromosome missegregation. An additional top2 mutation could restore centromeric chromatin integrity, suggesting a counterbalance between Top2 and these DXR factors in conferring doxorubicin resistance. Overall, this molecular basis for mitotic catastrophe associated with doxorubicin treatment will help to facilitate drug combinatorial usage in doxorubicin-related chemotherapeutic regimens.
Volume 5
Pages 8400
Published 2015-2-11
DOI 10.1038/srep08400
PII srep08400
PMID 25669599
PMC PMC4323662
MeSH Centromere / metabolism* Chromosomal Proteins, Non-Histone / metabolism Chromosome Aberrations Cluster Analysis DNA Topoisomerases, Type II / metabolism* Doxorubicin / pharmacology* Drug Resistance, Fungal* Epistasis, Genetic Gene Expression Regulation, Fungal Genetic Fitness* Mutation Schizosaccharomyces / drug effects* Schizosaccharomyces / physiology* Transcription, Genetic
IF 3.998
Times Cited 11
Yeast top2-342