Sgo1 as a "guardian spirit" for preventing colon tumorigenesis.

High-fidelity chromosome segregation during both mitosis and meiosis is essential for the propagation and inheritance of stable genomes. Defects in these fundamental processes promote aberrant chromosome segregation, which, in the absence of cell death, produces aneuploid progeny. In somatic cells, aneuploidy is a putative cancer-promoting event. In germ cells, aneuploidy can reduce reproductive fertility and promote the accumulation of trisomies, such as those associated with Down, Patau or Edward syndromes. In order for maintenance of genomic integrity, cells have an elaborate network of proteins that function during mitosis and meiosis to ensure accurate chromosome segregation. One such proposed mitotic regulator is shugoshin. Whereas budding yeast and Drosophila contain a single shugoshin gene, fission yeast and mammals have two paralogs (Sgo1 and Sgo2). The exact role of the shugoshin family of proteins during mitosis and meiosis has been somewhat elusive. Several functions have been proposed for Sgo1, including protecting centromeric cohesion through associating with PP2A phosphatase, ensuring attachment error correction through chromosome passenger complex positioning, maintaining centriole cohesion and mediating kinetochore microtubule attachment by interacting directly with spindle microtubules. Like Sgo1, Sgo2 has also been similarly implicated in centromeric cohesion and attachment error correction, although under different cellular circumstances than Sgo1. On the other hand, Sgo2, but not Sgo1, is thought to function during mitosis through binding spindle microtubules through its association with astrin and through binding Mad2. Until now, the physiological consequences of deregulated Sgo1 had been unknown.

In a previous issue of Cell Cycle, Yamada and colleagues set out to assess the cellular and physiological consequences of reduced Sgo1 expression, since mouse Sgo1 encodes an essential gene. Importantly, which functions of Sgo1 are required for cell viability and whether this occurs at centromeres or centrosomes remains unknown. One hint that centromeric, mitotic Sgo1 may not be required for viability, however, comes from the observation that interphase Sgo1 is sufficient for the establishment of centromeric cohesion. This raises the question of what the function of mitotic Sgo1 is, in addition to whether and how it contributes to chromosome segregation. Consistent with the reported roles of Sgo1, mouse embryonic fibroblasts haploinsufficient for Sgo1 harbored both amplified centrosomes as well as chromosomes that were improperly attached to spindle microtubules. Whether the attachment defect was due to aberrant geometries from centrosome amplification, reduced correction of defective kinetochore microtubule interactions or precocious separation of sister chromatids is not known.

Because diminished Sgo1 expression had been previously linked to human colon neoplastic lesions, Yamada and colleagues challenged Sgo1 heterozygous mice with AOM, a carcinogen that generates DNA damage to initiate colon carcinogenesis. Importantly, mice heterozygous for Sgo1 harbored 5-fold more colon adenomas than wild-type mice at 12 weeks after completion of AOM treatment. Rather intriguingly, mice haploinsufficient for Sgo1 were actually more prone to cell death in the colonic mucosa compared with wild-type mice, at least in the initial phase of the experiment. This is a first demonstration of enhanced cell death following carcinogen challenge in a chromosomally unstable murine model. However, it remains an open question how enhanced cell death, although only immediately following carcinogen challenge, might alter the delicate balance regulating cell proliferation vs. cell death to influence tumor progression. This relationship could have significant implications in tumor etiology, progression and aggressiveness.

In summary, this study provides a causal link between diminished Sgo1 expression and induction of carcinogen-induced colon tumorigenesis. Additionally, these experiments raise a number of intriguing questions concerning the molecular mechanism for how Sgo1 contributes to high-fidelity chromosome segregation. The study of Sgo1 in mammals continues the line of investigation that began with the study of a single shugoshin gene in budding yeast and will likely lead to an increased understanding of the multiple layers of regulation necessary for proper chromosome segregation.