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.
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