Chemical genomics approach to identify genes associated with sensitivity to rapamycin in the fission yeast Schizosaccharomyces pombe
Chemical genomics approach to identify genes associated with sensitivity to rapamycin in the fission yeast Schizosaccharomyces pombe
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DOI：
10.1111/gtc.12223
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发表时间：
2015-04-01
期刊：
影响因子：
2.1
通讯作者：
Sugiura, Reiko
中科院分区：
文献类型：
--
作者：
Doi, Akira;Fujimoto, Ayumi;Sugiura, Reiko
雷帕霉素及其衍生物具有免疫抑制和抗肿瘤双重特性，是一种极具吸引力的治疗策略。此外，雷帕霉素已被提议作为热量限制模拟物以延长各种生物体的寿命。裂殖酵母粟酒裂殖酵母（Schizoskillomycespombe，S.pombe）作为一种有价值的遗传模型系统，用于研究药物作用机制以及确定与药物敏感性或抗性相关的遗传背景。在这里，我们鉴定了缺失后调节粟酒裂殖酵母中雷帕霉素敏感菌株的基因。我们使用基因组缺失文库进行了雷帕霉素敏感突变体的化学基因组学筛选，该文库覆盖了所有非必需裂殖酵母基因的95.3%，并确认了59个基因是雷帕霉素敏感的。基因本体（GO）富集分析表明，雷帕霉素敏感菌株在调节tRNA修饰和线粒体的过程中高度富集，同时也富集了其他本体，包括细胞代谢过程、染色质组织、细胞周期、信号传导、翻译、转运等细胞过程。分析还表明，延长复合物的组分在敏感菌株中过多。在这里，所获得的数据将提供有价值的信息推测雷帕霉素的行动以及TORC信号，从而提出了一种策略，以提高敏感性雷帕霉素。
Rapamycin and its derivatives have now emerged as an attractive therapeutic strategy with both immunosuppressant and antitumor properties. In addition, rapamycin has been proposed as a calorie restriction mimetic to extend the life span of various organisms. The fission yeast Schizosaccharomyces pombe (S.pombe) serves as a valuable genetic model system to study the mechanism(s) of drug action as well as to determine genetic contexts associated with drug sensitivity or resistance. Here, we identified genes that when deleted modulate the rapamycin-sensitive strains in S.pombe. We carried out a chemical genomics screen for rapamycin-sensitive mutants using the genome-deletion library which covers 95.3% of all nonessential fission yeast genes and confirmed 59 genes to be rapamycin sensitive. Gene Ontology (GO) enrichment analysis showed that strains sensitive to rapamycin are highly enriched in processes regulating tRNA modification and mitochondria as well as other ontologies, including cellular metabolic process, chromatin organization, cell cycle, signaling, translation, transport and other cellular processes. Analysis also showed that components of the Elongator complex are overrepresented in the sensitive strains. Here, the data obtained will provide valuable information for speculation on the actions of rapamycin as well as on TORC signaling, thereby presenting a strategy to enhance sensitivity to rapamycin.