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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, defining specific mechanisms and functions of sphingolipids in cell cycle regulation is missing. 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, GIM4) as synthetically lethal with ISC1. The second group, to which ISC1 belongs, comprises genes involved in the spindle checkpoint (BUB1, MAD1, BIM1, 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. [ABSTRACT FROM AUTHOR]