| 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
|
|
WOS Category
|
BIOCHEMISTRY & MOLECULAR BIOLOGY
|
| Resource |
| Yeast |
top2-342 |
