Mechanisms controlling chromosome stability during cell division

Shugoshin (Sgo1) functions as a protector of centromeric cohesion of sister chromatids in higher eukaryotes. Here, we provide novel evidence that Sgo1 plays a role in the centrosome cycle during mitosis. Sgo1 depletion via RNA interference induced the formation of multiple centrosome-like structures in mitotic cells that result from the separation of paired centrioles. Sgo1+/-- mitotic murine embryonic fibroblasts display split centrosomes. Localization of two major endogenous splice variants of Sgo1 indicated that the smaller variant, hsSgo1, was found at the centrosome in interphase and at spindle poles during mitosis. Ectopic expression of hsSgo1 suppressed centriole splitting. RNAi-mediated knockdown of Plk1 or mutation of putative Plk1 phosphorylation sites in hsSgo1 abolished its spindle pole localization. Plk1 depletion also suppressed centriole splitting and chromosome missegregation induced by the dominant negative mutant Sgo11-196. Our studies strongly suggest that hsSgo1 plays an essential role in protecting centriole cohesion, which is partly mediated by Plk1. Sgo1 functions in maintaining the integrity of both the kinetochores and spindle poles and that these bifurcate functions are mediated by its spliced variants, respectively. Its importance to normal chromosomal segregation suggests that dysregulated function of Sgo1 may be one of the major underlying causes of chromosomal instability. Such aberrations correlate in some cases with the development of cancer.