title: Fitness profiling links topoisomerase II regulation of centromeric integrity to doxorubicin resistance in fission yeast.
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.
authors: 1] Department of Biochemistry, National University of Singapore, Singapore 117597 [2] National University Health System (NUHS), Singapore.
authors: Thi Thuy Trang
authors: TT
authors: Nguyen
authors: 1] Department of Biochemistry, National University of Singapore, Singapore 117597 [2] National University Health System (NUHS), Singapore.
authors: Julia Sze Lynn
authors: JS
authors: Lim
authors: 1] Department of Biochemistry, National University of Singapore, Singapore 117597 [2] National University Health System (NUHS), Singapore.
authors: Richard Ming Yi
authors: RM
authors: Tang
authors: 1] NUS Graduate School for Integrative Sciences and Engineering [2] Department of Mathematics, National University of Singapore, Singapore 119076.
authors: Louxin
authors: L
authors: Zhang
authors: 1] Department of Biochemistry, National University of Singapore, Singapore 117597 [2] National University Health System (NUHS), Singapore [3] Synthetic Biology Research Consortium, National University of Singapore [4] NUS Graduate School for Integrative Sciences and Engineering.
authors: Ee Sin
authors: ES
authors: Chen
mesh_terms: D002503:Centromere / Q000378:metabolism*; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D002869:Chromosome Aberrations; D016000:Cluster Analysis; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology*; D025141:Drug Resistance, Fungal; D004843:Epistasis, Genetic; D015966:Gene Expression Regulation, Fungal; D056084:Genetic Fitness; D009154:Mutation; D012568:Schizosaccharomyces / Q000187:drug effects* / Q000502:physiology*; D014158:Transcription, Genetic
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D004317:Doxorubicin; D004250:DNA Topoisomerases, Type II