Nuclear envelope expansion is critical for proper chromosomal segregation during a closed mitosis

Abstract

We have 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 have identified a phosphorium ylide-based compound Cutin-1 which inhibits nuclear envelope expansion and nuclear elongation during the closed mitosis of fission yeast, and have shown that its target is the beta 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 are only transiently separated during mitosis, and nucleoli separation was defective. Subsequently sister chromatids re-associate 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.