Chemical suppression of defects in mitotic spindle assembly, redox control, and sterol biosynthesis by hydroxyurea.
Chemical suppression of defects in mitotic spindle assembly, redox control, and sterol biosynthesis by hydroxyurea.
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DOI：
10.1534/g3.113.009100
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发表时间：
2014-01-10
期刊：
影响因子：
--
通讯作者：
Feng W
中科院分区：
文献类型：
--
作者：
McCulley A;Haarer B;Viggiano S;Karchin J;Feng W
我们描述了对酿酒酵母基因组中迄今为止被忽视的一类化学-遗传相互作用的系统搜索结果，这种相互作用存在于有害的基因突变和可以改善而不是加剧这种损害的化学/药物之间。我们将这种类型的相互作用称为“化学抑制”。我们的工作是基于这样的假设：某一类突变体的基因组不稳定性可以通过使用化学品/药物的轻度复制抑制来缓解。我们查询了一组条件致死（即温度敏感）等位基因，这些等位基因代表了那些突变体的 40% 酵母必需基因，这些突变体的生长缺陷可以在限制温度下被羟基脲（HU）（一种有效的 DNA 复制抑制剂）抑制。出乎意料的是，我们发现了许多在 DNA 复制以外的多种细胞途径中存在缺陷的突变体。在这里，我们报告说，HU 在有丝分裂染色体分离过程中抑制着丝粒-微管附着途径缺陷的选定突变体。 HU 还通过提供氧化当量来抑制内质网硫醇氧化酶缺陷的 ero1-1 突变体。最后，我们报告说，HU 通过调节铁稳态来抑制 C-3 甾醇脱氢酶缺陷的 erg26-1 突变体，进而影响麦角甾醇生物合成。我们进一步证明，携带 erg26-1 突变的细胞显示线粒体 DNA 丢失率增加，并延迟 G1 到 S 期的转变。我们的结论是，系统地收集基因毒性药物对酵母突变体的“化学抑制”概要不仅能够识别化学物质和基因的新功能，而且对人类抗癌干预的预防措施具有深远的影响。
We describe the results of a systematic search for a class of hitherto-overlooked chemical-genetic interactions in the Saccharomyces cerevisiae genome, which exists between a detrimental genetic mutation and a chemical/drug that can ameliorate, rather than exacerbate, that detriment. We refer to this type of interaction as “chemical suppression.” Our work was driven by the hypothesis that genome instability in a certain class of mutants could be alleviated by mild replication inhibition using chemicals/drugs. We queried a collection of conditionally lethal, i.e., temperature-sensitive, alleles representing 40% of the yeast essential genes for those mutants whose growth defect can be suppressed by hydroxyurea (HU), known as a potent DNA replication inhibitor, at the restrictive temperature. Unexpectedly, we identified a number of mutants defective in diverse cellular pathways other than DNA replication. Here we report that HU suppresses selected mutants defective in the kinetochore-microtubule attachment pathway during mitotic chromosome segregation. HU also suppresses an ero1-1 mutant defective for a thiol oxidase of the endoplasmic reticulum by providing oxidation equivalents. Finally, we report that HU suppresses an erg26-1 mutant defective for a C-3 sterol dehydrogenase through regulating iron homeostasis and in turn impacting ergosterol biosynthesis. We further demonstrate that cells carrying the erg26-1 mutation show an increased rate of mitochondrial DNA loss and delayed G1 to S phase transition. We conclude that systematic gathering of a compendium of “chemical suppression” of yeast mutants by genotoxic drugs will not only enable the identification of novel functions of both chemicals and genes, but also have profound implications in cautionary measures of anticancer intervention in humans.
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影响因子：
56.9
作者：
Hillenmeyer, Maureen E.;Fung, Eula;Giaever, Guri
通讯作者：
Giaever, Guri
DOI：
10.1073/pnas.0506448103
发表时间：
2006-01-10
影响因子：
11.1
作者：
Gross, E;Sevier, CS;Fass, D
通讯作者：
Fass, D
影响因子：
3.1
作者：
Dubacq, C;Chevalier, A;Mann, C
通讯作者：
Mann, C
影响因子：
16
作者：
Frand, AR;Kaiser, CA
通讯作者：
Kaiser, CA
影响因子：
7.8
作者：
Bicknell, Alicia A.;Babour, Anna;Niwa, Maho
通讯作者：
Niwa, Maho