A novel function of Shugoshin-1 (Sgo1) in maintaining spindle pole integrity

LB-260 Errors occurred in mitosis can result in aneuploidy, a hallmark of human cancer. Mitotic fidelity is ensured by the spindle checkpoint which monitors proper attachment of mitotic spindles to condensed chromosomes. Defective coordination between the kinetochores and the spindle pole, two important mitotic apparatuses, during mitosis can impair chromosome segregation. Efforts have been made to discover molecular entities that coordinate the action of kinetochores and spindle poles during mitosis. Shugoshin-1 (Sgo1) is an evolutionarily conserved protein, functioning to timely release centromeric cohesin under the surveillance of the spindle checkpoint in early mitosis. Truncated Sgo1 (probably defective) was found overexpressed in multiple forms of cancers. Here we demonstrate a novel function of human sSgo1, a major splice isoform of Sgo1, at the spindle poles. sSgo1 localizes to the centrosome during interphase and to the spindle poles in mitosis. Sgo1 depletion via RNA interference (RNAi) induces the formation of multiple centrosome-like structures in early mitosis that primarily result from the separation of paired centrioles (referred as centrosome splitting). Murine embryonic fibroblasts (MEFs) derived from Sgo1 heterozygous (Sgo1+/-) mice also display split centrosomes despite of relatively normal mitotic progression. Ectopic expression of an sSgo1 construct efficiently suppresses centrosome splitting in Sgo1 siRNA-transfected cells and Sgo1+/- MEF. Combined, our studies strongly suggest a bifurcate function of Sgo1 at centromeres and spindle poles. Sgo1 deficiency results in both chromosomal and centrosomal instabilities. Given the importance of sSgo1 in regulating the spindle pole integrity, it is necessary to further investigate whether defective sSgo1 during mitosis has any pathological consequences.