@article{3afd46fe8aea4739a9b0d76f8ae18c92,
title = "Yeast sphingolipid phospholipase gene ISC1 regulates the spindle checkpoint by a CDC55-dependent mechanism",
abstract = "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 CDC55mediated nuclear functions.",
keywords = "Budding yeast, CDC55, Cell cycle, Ceramide, Hydroxyurea, ISC1, Phosphoproteomics, SWE1, Spindle checkpoint",
author = "Nabil Matmati and Hassan, {Bachar H.} and Jihui Ren and Shamssedine, {Ashraf A.} and Eunmi Jeong and Baasil Shariff and Justin Snider and R{\o}dk{\ae}r, {Steven V.} and Guocai Chen and Mohanty, {Bidyut K.} and {Jim Zheng}, W. and Obeid, {Lina M.} and Martin R{\o}ssel-Larsen and F{\ae}rgeman, {Nils J.} and Hannun, {Yusuf A.}",
note = "Funding Information: This work was supported by NIH grant GM118128 to Y.A.H. and grants P20 RR017696, P20 RR017677, CPRIT RP170668, and LM 010680 to W.J.Z. Microscopy was performed at the Central Microscopy Imaging Center (CMIC) at Stony Brook University. We thank Guowei Tian for his help and support in microscopy and Nancy Hollingsworth at Stony Brook University, Department of Biochemistry and Cell Biology, for providing us with the K6745 strain. We also thank the lipidomic core at Stony Brook University for the lipid analysis. We thank the KEGG/GenomeNet team for granting copyright permission to publish Fig. 1B. Author contributions are as follows: conceptualization, N.M., B.H.H., W.J.Z., and Y.A.H.; methodology and investigation, N.M., B.H.H., A.A.S., E.J., B.S., and G.C.; genetic interaction analysis, W.J.Z.; phosphoproteomics analysis, N.M., B.H.H., J.R., A.A.S., J.S., S.V.R., M.R.L., and N.J.F.; writing of original draft, N.M. and Y.A.H.; writing, review, and editing, N.M., B.H.H., J.R., B.K.M., W.J.Z., N.J.F., L.M.O., and Y.A.H.; and funding acquisition, Y.A.H. We declare no competing interests. Publisher Copyright: {\textcopyright} 2020 American Society for Microbiology. All Rights Reserved.",
year = "2020",
month = jun,
day = "1",
doi = "10.1128/MCB.00340-19",
language = "English (US)",
volume = "40",
journal = "Molecular and Cellular Biology",
issn = "0270-7306",
publisher = "American Society for Microbiology",
number = "12",
}