<i>S. pombe</i> Mis4 is required for exit from G0 as it is necessary for full nuclear separation during the subsequent M phase

The evolutionarily conserved Mis4 protein 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 multisystem disorder called Cornelia de Lange syndrome. We have 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. Here, we show that Mis4 is not required for cells to enter G0 phase, but is essential for them to exit from it. When resuming mitosis after a passage of G0, mis4 mutant cells segregated sister chromatids successfully, but failed to separate daughter nuclei completely and consequently formed dikaryon-like cells. These findings suggest a novel role for Mis4/NIPBL in quiescent cells, which is a prerequisite for full nuclear separation upon resumed mitosis. As most human cells are in a quiescent state, this study might facilitate development of novel therapies for human diseases caused by Mis4/NIPBL deficiency.