In quiescent G0 phase, Schizosaccharomyces pombe Mis4 ensures full nuclear separation during the subsequent M phase

Abstract

Evolutionarily conserved Mis4 establishes cohesion between replicated sister chromatids in vegetatively proliferating cells. In the fission yeast, Schizosaccharomyces pombe, defects in Mis4 lead to premature separation of sister chromatids, resulting in fatal chromosome mis-segregation during mitosis. In humans, NIPBL, an ortholog of Mis4, is responsible for a severe multisystem disorder called Cornelia de Lange syndrome. We previously reported that Mis4 is also essential in non-proliferating quiescent cells. Whereas wild-type fission yeast cells can maintain high viability for long periods without cell division in the quiescent G0 phase, mis4-450 mutant cells cannot. In this report, we show that Mis4 is not required for cells to enter G0 phase, but is essential to exit from it. When resuming mitosis after passage of G0, mis4 mutant cells segregated sister chromatid successfully, but insufficiently separated daughter nuclei consequently formed dikaryon-like cells. These findings suggest a novel role of Mis4/NIPBL in non-dividing quiescent cells, which is prerequisite for full nuclear separation upon resumed mitosis. As most human cells are in the quiescent state, this study may facilitate development of novel therapies for human diseases caused by Mis4/NIPBL deficiency.