Defects in the spindle assembly checkpoint (SAC) can lead to aneuploidy and cancer. Sphingolipids have important roles in many cellular functions, including cell cycle regulation and apoptosis. However, the specific mechanisms and functions of sphingolipids in cell cycle regulation have not been elucidated. Using analysis of concordance for synthetic lethality for the yeast sphingolipid phospholipase ISC1, we identified two groups of genes. The first comprises genes involved in chromosome segregation and stability (CSM3, CTF4, YKE2, DCC1, and GIM4) as synthetically lethal with ISC1 The second group, to which ISC1 belongs, comprises genes involved in the spindle checkpoint (BUB1, MAD1, BIM1, and KAR3), and they all share the same synthetic lethality with the first group. We demonstrate that spindle checkpoint genes act upstream of Isc1, and their deletion phenocopies that of ISC1 Reciprocally, ISC1 deletion mutants were sensitive to benomyl, indicating a SAC defect. Similar to BUB1 deletion, ISC1 deletion prevents spindle elongation in hydroxyurea-treated cells. Mechanistically, PP2A-Cdc55 ceramide-activated phosphatase was found to act downstream of Isc1, thus coupling the spindle checkpoint genes and Isc1 to CDC55-mediated nuclear functions.

中文翻译：

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酵母鞘脂磷脂酶基因 ISC1 通过 CDC55 依赖性机制调节纺锤体检查点。

纺锤体组装检查点 (SAC) 的缺陷可导致非整倍体和癌症。鞘脂在许多细胞功能中发挥重要作用，包括细胞周期调节和细胞凋亡。然而，鞘脂在细胞周期调控中的具体机制和功能尚未阐明。通过对酵母鞘脂磷脂酶 ISC1 合成致死率的一致性分析，我们确定了两组基因。第一组包括涉及染色体分离和稳定性的基因（CSM3、CTF4、YKE2、DCC1 和 GIM4），与 ISC1 具有综合致死性。第二组是 ISC1 所属的基因，包括涉及纺锤体检查点的基因（BUB1、MAD1、BIM1、和 KAR3），并且它们都与第一组具有相同的合成致死率。我们证明纺锤体检查点基因作用于 Isc1 上游，并且它们的缺失表型与 ISC1 相似。相反，ISC1 缺失突变体对苯菌灵敏感，表明 SAC 缺陷。与 BUB1 缺失类似，ISC1 缺失可防止羟基脲处理的细胞中纺锤体伸长。从机制上讲，PP2A-Cdc55 神经酰胺激活磷酸酶被发现在 Isc1 下游发挥作用，从而将纺锤体检查点基因和 Isc1 与 CDC55 介导的核功能偶联。