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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Molecular Oncogenesis Study Section (MONC)
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Mietz, Judy
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New York University
Public Health & Prev Medicine
Schools of Medicine
New York
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Wu, Meng; Yang, Feikun; Ren, Zhihua et al. (2014) Identification of the nuclear localization signal of SALL4B, a stem cell transcription factor. Cell Cycle 13:1456-62
Choi, Byeong Hyeok; Pagano, Michele; Dai, Wei (2014) Plk1 protein phosphorylates phosphatase and tensin homolog (PTEN) and regulates its mitotic activity during the cell cycle. J Biol Chem 289:14066-74
Yao, Yixin; Lu, Yinghua; Chen, Wen-Chi et al. (2014) Cobalt and nickel stabilize stem cell transcription factor OCT4 through modulating its sumoylation and ubiquitination. PLoS One 9:e86620
Tsui, S; Dai, W; Lu, L (2014) CCCTC-binding factor mediates effects of glucose on beta cell survival. Cell Prolif 47:28-37
Choi, Byeong Hyeok; Pagano, Michele; Huang, Chaunshu et al. (2014) Cdh1, a substrate-recruiting component of anaphase-promoting complex/cyclosome (APC/C) ubiquitin E3 ligase, specifically interacts with phosphatase and tensin homolog (PTEN) and promotes its removal from chromatin. J Biol Chem 289:17951-9
Choi, Byeong Hyeok; Chen, Yan; Dai, Wei (2013) Chromatin PTEN is involved in DNA damage response partly through regulating Rad52 sumoylation. Cell Cycle 12:3442-7
Yao, Yixin; Dai, Wei (2012) Mitotic checkpoint control and chromatin remodeling. Front Biosci (Landmark Ed) 17:976-83
Yang, Feikun; Hu, Liyan; Chen, Cheng et al. (2012) BubR1 is modified by sumoylation during mitotic progression. J Biol Chem 287:4875-82
Yamada, Hiroshi Y; Yao, Yixin; Wang, Xiaoxing et al. (2012) Haploinsufficiency of SGO1 results in deregulated centrosome dynamics, enhanced chromosomal instability and colon tumorigenesis. Cell Cycle 11:479-88
Yang, Feikun; Huang, Ying; Dai, Wei (2012) Sumoylated BubR1 plays an important role in chromosome segregation and mitotic timing. Cell Cycle 11:797-806

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