An underlying genomic instability is required for the generation of multiple lesions that are characteristic of cancer. Aneuploidy, a common form of genomic instability, is a direct result of chromosomal missegregation during mitosis. Over the course of evolution, eukaryotic cells have developed sophisticated molecular mechanisms to maintain the physical association between sister chromatids during the S, G2, and early mitotic phases of the cell cycle until the onset of anaphase to prevent the adverse consequences of abnormal chromosomal segregation. Sister chromatid cohesion is largely achieved by the cohesin complex. In vertebrates, cohesin dissociates from the chromosome arm during prophase, but not from its centromere. Recent studies revealed that Shugoshin-1 (Sgo1), an evolutionarily conserved protein, protects centromeric cohesin during early mitosis and that the suppression of Sgo1 activity results in premature chromatid separation and massive mitotic arrest, followed by mitotic catastrophe. We recently found sSgo1--a major splice variant --exhibits no kinetochore localization and instead, it is enriched at the spindle poles and mitotic spindles during mitosis, suggesting a role for this protein in centrosome dynamics. Supporting this, RNAi- mediated Sgo1 knock-down results in depletion of both isoforms (namely, the full length Sgo1 and the short sSgo1), as well as in the formation of multiple spindle poles in mitotic cells. Given two distinct activities associated with Sgo1, we hypothesize that Sgo1 protects cohesion of sister chromatids and centrioles, both of which are central to accurate segregation of chromosomes, maintenance of chromosomal stability, and suppression of aneuploidy and tumorigenesis in vivo. To test this hypothesis, we propose to (i) study whether Sgo1's roles in centromeric cohesion and spindle pole/microtubule dynamics are each mediated by a major splice variant, (ii) determine cellular and molecular mechanisms by which sSgo1 regulates spindle pole integrity during mitosis, and (iii) investigate whether Sgo1 down-regulation or its haplo-insufficiency contributes to oncogenic transformation both in vivo and in vitro. Given the importance of sister chromatid and centriole cohesion in the maintenance of genomic stability, further characterization of Sgo1/sSgo1 and their regulation may provide invaluable insights into the pathogenesis of cancer as well as a new target for therapeutic intervention. ? ? ? ? ? ?
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