酵母鞘脂磷脂酶基因通过依赖-β的机制调控纺锤体检查点。
Yeast Sphingolipid Phospholipase Gene Regulates the Spindle Checkpoint by a -Dependent Mechanism.
机构信息
The Stony Brook University Cancer Center, Stony Brook University, Stony Brook, New York, USA.
Department of Medicine, Stony Brook University, Stony Brook, New York, USA.
出版信息
Mol Cell Biol. 2020 May 28;40(12). doi: 10.1128/MCB.00340-19.
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 , we identified two groups of genes. The first comprises genes involved in chromosome segregation and stability (, , , , and ) as synthetically lethal with The second group, to which belongs, comprises genes involved in the spindle checkpoint (, , , and ), 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 Reciprocally, deletion mutants were sensitive to benomyl, indicating a SAC defect. Similar to deletion, 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 -mediated nuclear functions.
纺锤体装配检查点（SAC）缺陷可导致非整倍体和癌症。神经鞘脂在许多细胞功能中具有重要作用，包括细胞周期调控和细胞凋亡。然而，神经鞘脂在细胞周期调控中的具体机制和功能尚不清楚。通过对酵母神经鞘脂磷酸酶的合成致死性分析的一致性分析，我们鉴定出两组基因。第一组包括参与染色体分离和稳定性的基因（，，，，和），它们与 具有合成致死性。第二组，其中包括 ，涉及纺锤体检查点（，，，和），它们都与第一组具有相同的合成致死性。我们证明纺锤体检查点基因在上游作用于 Isc1，其缺失表型类似于 的缺失。相反， 缺失突变体对苯并咪唑敏感，表明 SAC 缺陷。类似于 的缺失， 的缺失可防止羟基脲处理的细胞中的纺锤体伸长。从机制上讲，发现 PP2A-Cdc55 神经酰胺激活磷酸酶位于 Isc1 下游，从而将纺锤体检查点基因和 Isc1 与 介导的核功能偶联。
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