title: Nuclear envelope expansion is crucial for proper chromosomal segregation during a closed mitosis.
abstract: Here, we screened a 10,371 library of diverse molecules using a drug-sensitive fission yeast strain to identify compounds which cause defects in chromosome segregation during mitosis. We identified a phosphorium-ylide-based compound Cutin-1 which inhibits nuclear envelope expansion and nuclear elongation during the closed mitosis of fission yeast, and showed that its target is the β-subunit of fatty acid synthase. A point mutation in the dehydratase domain of Fas1 conferred in vivo and in vitro resistance to Cutin-1. Time-lapse photomicrography showed that the bulk of the chromosomes were only transiently separated during mitosis, and nucleoli separation was defective. Subsequently sister chromatids re-associated leading to chromosomal mis-segregation. These segregation defects were reduced when the nuclear volume was increased and were increased when the nuclear volume was reduced. We propose that there needs to be sufficient nuclear volume to allow the nuclear elongation necessary during a closed mitosis to take place for proper chromosome segregation, and that inhibition of fatty acid synthase compromises nuclear elongation and leads to defects in chromosomal segregation.
authors: Laboratory of Yeast Genetics and Cell Biology, The Rockefeller University, New York, NY 10065, USA ai.takemoto@jfcr.or.jp.
authors: Ai
authors: A
authors: Takemoto
authors: Laboratory of Chemistry and Cell Biology, Rockefeller University, New York, NY 10065, USA Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan.
authors: Shigehiro A
authors: SA
authors: Kawashima
authors: The Francis Crick Institute, Lincoln's Inn Fields Laboratories, London NW1 2BE, UK.
authors: Juan-Juan
authors: JJ
authors: Li
authors: The Francis Crick Institute, Lincoln's Inn Fields Laboratories, London NW1 2BE, UK.
authors: Linda
authors: L
authors: Jeffery
authors: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan.
authors: Kenzo
authors: K
authors: Yamatsugu
authors: Department of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY 10021, USA.
authors: Olivier
authors: O
authors: Elemento
authors: Laboratory of Yeast Genetics and Cell Biology, The Rockefeller University, New York, NY 10065, USA The Francis Crick Institute, Lincoln's Inn Fields Laboratories, London NW1 2BE, UK.
authors: Paul
authors: P
authors: Nurse
mesh_terms: D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D020090:Chromosome Segregation; D015825:Chromosomes, Fungal / Q000235:genetics* / Q000378:metabolism; D008938:Mitosis; D009685:Nuclear Envelope / Q000235:genetics / Q000378:metabolism*; D012568:Schizosaccharomyces / Q000166:cytology* / Q000235:genetics / Q000378:metabolism; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D029702:Schizosaccharomyces pombe Proteins
keywords: Chromosome segregation; Fatty acid synthase; Mitosis; Nuclear envelope expansion