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首页> 外文期刊>Molecular and Cellular Biology >Genetic Analysis of the Kinetochore DASH Complex Reveals an Antagonistic Relationship with the Ras/Protein Kinase A Pathway and a Novel Subunit Required for Ask1 Association
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Genetic Analysis of the Kinetochore DASH Complex Reveals an Antagonistic Relationship with the Ras/Protein Kinase A Pathway and a Novel Subunit Required for Ask1 Association

机译：线粒体DASH复合体的遗传分析揭示了与Ras /蛋白激酶A途径和Ask1关联所需的新型亚基的拮抗关系。

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DASH is a microtubule- and kinetochore-associated complex required for proper chromosome segregation and bipolar attachment of sister chromatids on the mitotic spindle. We have undertaken a genetic and biochemical analysis of the DASH complex and uncovered a strong genetic interaction of DASH with the Ras/protein kinase A (PKA) pathway. Overexpression of PDE2 or deletion of RAS2 rescued the temperature sensitivity of ask1-3 mutants. Ras2 negatively regulates DASH through the PKA pathway. Constitutive PKA activity caused by mutation of the negative regulator BCY1 is toxic to DASH mutants such as ask1 and dam1. In addition, we have discovered two novel subunits of DASH, Hsk2 and Hsk3 (helper of Ask1), which are microproteins of fewer than 75 amino acids, as dosage suppressors of ask1 mutants. These are essential genes that colocalize with DASH components on spindles and kinetochores and are present in the DASH complex. Mutants in hsk3 arrest cells in mitosis with short spindles and broken spindle structures characteristic of other DASH mutants. Hsk3 is critical for the integrity of the DASH complex because in hsk3 mutants the association of Dam1, Duo1, Spc34, and Spc19 with Ask1 is greatly diminished. We propose that Hsk3 acts to incorporate Ask1 into the DASH complex.
机译：DASH是微管和动线粒体相关的复合物，用于染色体的正确分离和姐妹染色单体在有丝分裂纺锤体上的双极附着。我们已经对DASH复合物进行了遗传和生化分析，并发现DASH与Ras /蛋白激酶A（PKA）途径之间有很强的遗传相互作用。 PDE2 的过表达或 RAS2 的缺失挽救了 ask1 - 3 突变体的温度敏感性。 Ras2通过PKA途径负调控DASH。负调控因子 BCY1 突变引起的本构PKA活性对DASH突变体如 ask1 和 dam1 有毒。此外，我们发现了DASH的两个新亚基Hsk2和Hsk3（Ask1的辅助分子），它们是少于75个氨基酸的微蛋白，是 ask1 突变体的剂量抑制剂。这些是必不可少的基因，它们与纺锤体和动植物的DASH成分共定位，并存在于DASH复合物中。 hsk3 中的突变体将细胞停在有丝分裂中，具有短梭形和其他DASH突变体特有的纺锤形结构。 Hsk3对于DASH复合体的完整性至关重要，因为在 hsk3 突变体中，Dam1，Duo1，Spc34和Spc19与Ask1的关联大大减少了。我们建议Hsk3的作用是将Ask1合并到DASH复合体中。

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