Impaired coenzyme A synthesis in fission yeast causes defective mitosis, quiescence-exit failure, histone hypoacetylation and fragile DNA.
Impaired coenzyme A synthesis in fission yeast causes defective mitosis, quiescence-exit failure, histone hypoacetylation and fragile DNA.
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DOI：
10.1098/rsob.120117
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发表时间：
2012-09
期刊：
影响因子：
5.8
通讯作者：
Yanagida M
中科院分区：
文献类型：
--
作者：
Nakamura T;Pluskal T;Nakaseko Y;Yanagida M
辅酶A(CoA)的生物合成需要在裂解酵母中使用泛酸和半胱氨酸进行五步反应。辅酶A含有一个硫醇(SH)基团，它与羧酸反应生成硫代酯，产生乙酰辅酶A等酰基活化的辅酶A。乙酰辅酶A对于能量代谢和蛋白质乙酰化是必不可少的，在高等真核生物中，对于神经递质的产生也是必不可少的。我们分离到了一株新的温度敏感菌株ppc1-537，该菌株突变于磷酸泛硫酰半胱氨酸合成酶的催化区域(命名为Ppc1)，该酶是辅酶A合成所必需的。在允许的温度下，突变株对泛酸营养不良，表现出辅酶A、乙酰辅酶A和组蛋白乙酰化水平的显著降低。此外，ppc1-537突变细胞未能使细胞从静止状态恢复增殖。因此，PPC1是一种超级家务基因的产物。Ppc1-537突变体显示出与6个组蛋白脱乙酰酶突变体中的5个组合的合成致死缺陷，而sir2缺失例外地挽救了ppc1-537的表型。在同步培养中，Pppc1-537细胞可以进入S期，但由于姐妹着丝粒/着丝粒分离和核分裂失败而失去活力。此外，ppc1-537突变体的双链断裂修复是有缺陷的，产生脆弱的DNA断裂，这可能是由于组蛋白乙酰化减少所致。辅酶A支持的代谢因此控制着染色体DNA的状态。
Biosynthesis of coenzyme A (CoA) requires a five-step process using pantothenate and cysteine in the fission yeast Schizosaccharomyces pombe. CoA contains a thiol (SH) group, which reacts with carboxylic acid to form thioesters, giving rise to acyl-activated CoAs such as acetyl-CoA. Acetyl-CoA is essential for energy metabolism and protein acetylation, and, in higher eukaryotes, for the production of neurotransmitters. We isolated a novel S. pombe temperature-sensitive strain ppc1-537 mutated in the catalytic region of phosphopantothenoylcysteine synthetase (designated Ppc1), which is essential for CoA synthesis. The mutant becomes auxotrophic to pantothenate at permissive temperature, displaying greatly decreased levels of CoA, acetyl-CoA and histone acetylation. Moreover, ppc1-537 mutant cells failed to restore proliferation from quiescence. Ppc1 is thus the product of a super-housekeeping gene. The ppc1-537 mutant showed combined synthetic lethal defects with five of six histone deacetylase mutants, whereas sir2 deletion exceptionally rescued the ppc1-537 phenotype. In synchronous cultures, ppc1-537 cells can proceed to the S phase, but lose viability during mitosis failing in sister centromere/kinetochore segregation and nuclear division. Additionally, double-strand break repair is defective in the ppc1-537 mutant, producing fragile broken DNA, probably owing to diminished histone acetylation. The CoA-supported metabolism thus controls the state of chromosome DNA.
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影响因子：
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作者：
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通讯作者：
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