Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

A novel tumor-derived SGOL1 variant causes abnormal mitosis and unstable chromatid cohesion

Oncogene volume 30, pages 4453–4463 (2011)Cite this article

Subjects

Abstract

Mitosis is the most conspicuous cell cycle phase, because it is the phase in which the dynamic physical distributions of cellular components into the two daughter cells occur. The separation of sister chromatids is especially important during mitosis, because of the extreme accuracy required for distribution to the next generation of cells. Shugoshin-like 1 (SGOL1) is a key protein in protecting sister chromatids from precocious separation. We have reported finding that chromosome instability is more likely in SGOL1-downregulated colorectal cancers, but it is still unknown whether there is an association between cancer and SGOL1 transcript variation. Here, we identified a novel SGOL1 variant, SGOL1-P1, in human colon cancer. The SGOL1-P1 transcript contains an exon-skip of exon 3 that results in a stop codon occurring within exon 4. Overexpression of SGOL1-P1 in HCT116 cells resulted in an increased number of cells with aberrant chromosome alignment, precociously separated chromatids and delayed mitotic progression, occasionally followed by inaccurate distribution of the chromosomes. These phenotypes, observed when SGOL1-P1 was present, were also observed very frequently in SGOL1-knockdown cells. Furthermore, the overexpression of SGOL1-P1 inhibited the localization of endogenous SGOL1 and cohesin subunit RAD21/SCC1 to the centromere. These results suggest that SGOL1-P1 may function as a negative factor to native SGOL1, and that abundant expression of SGOL1-P1 may be responsible for chromosomal instability.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  • Bharadwaj R, Yu H . (2004). The spindle checkpoint, aneuploidy, and cancer. Oncogene 23: 2016–2027.

    Article  CAS  Google Scholar 

  • Clift D, Bizzari F, Marston AL . (2009). Shugoshin prevents cohesin cleavage by PP2A(Cdc55)-dependent inhibition of separase. Genes Dev 23: 766–780.

    Article  CAS  Google Scholar 

  • Dai J, Kateneva AV, Higgins JM . (2009). Studies of haspin-depleted cells reveal that spindle-pole integrity in mitosis requires chromosome cohesion. J Cell Sci 122: 4168–4176.

    Article  CAS  Google Scholar 

  • Eot-Houllier G, Fulcrand G, Watanabe Y, Magnaghi-Jaulin L, Jaulin C . (2008). Histone deacetylase 3 is required for centromeric H3K4 deacetylation and sister chromatid cohesion. Genes Dev 22: 2639–2644.

    Article  CAS  Google Scholar 

  • Gisselsson D, Bjork J, Hoglund M, Mertens F, Dal Cin P, Akerman M et al. (2001). Abnormal nuclear shape in solid tumors reflects mitotic instability. Am J Pathol 158: 199–206.

    Article  CAS  Google Scholar 

  • Goldstein LS . (1980). Mechanisms of chromosome orientation revealed by two meiotic mutants in Drosophila melanogaster. Chromosoma 78: 79–111.

    Article  CAS  Google Scholar 

  • Grady WM . (2004). Genomic instability and colon cancer. Cancer Metastasis Rev 23: 11–27.

    Article  CAS  Google Scholar 

  • Hauf S, Waizenegger IC, Peters JM . (2001). Cohesin cleavage by separase required for anaphase and cytokinesis in human cells. Science 293: 1320–1323.

    Article  CAS  Google Scholar 

  • Iwaizumi M, Shinmura K, Mori H, Yamada H, Suzuki M, Kitayama Y et al. (2009). Human Sgo1 downregulation leads to chromosomal instability in colorectal cancer. Gut 58: 249–260.

    Article  CAS  Google Scholar 

  • Kahyo T, Mostoslavsky R, Goto M, Setou M . (2008). Sirtuin-mediated deacetylation pathway stabilizes Werner syndrome protein. FEBS Lett 582: 2479–2483.

    Article  CAS  Google Scholar 

  • Kanda T, Sullivan KF, Wahl GM . (1998). Histone-GFP fusion protein enables sensitive analysis of chromosome dynamics in living mammalian cells. Curr Biol 8: 377–385.

    Article  CAS  Google Scholar 

  • Kapoor TM, Lampson MA, Hergert P, Cameron L, Cimini D, Salmon ED et al. (2006). Chromosomes can congress to the metaphase plate before biorientation. Science 311: 388–391.

    Article  CAS  Google Scholar 

  • Karamysheva Z, Diaz-Martinez LA, Crow SE, Li B, Yu H . (2009). Multiple anaphase-promoting complex/cyclosome degrons mediate the degradation of human Sgo1. J Biol Chem 284: 1772–1780.

    Article  CAS  Google Scholar 

  • Kawashima SA, Yamagishi Y, Honda T, Ishiguro K, Watanabe Y . (2010). Phosphorylation of H2A by Bub1 prevents chromosomal instability through localizing shugoshin. Science 327: 172–177.

    Article  CAS  Google Scholar 

  • Kerrebrock AW, Moore DP, Wu JS, Orr-Weaver TL . (1995). Mei-S332, a Drosophila protein required for sister-chromatid cohesion, can localize to meiotic centromere regions. Cell 83: 247–256.

    Article  CAS  Google Scholar 

  • Kienitz A, Vogel C, Morales I, Muller R, Bastians H . (2005). Partial downregulation of MAD1 causes spindle checkpoint inactivation and aneuploidy, but does not confer resistance towards taxol. Oncogene 24: 4301–4310.

    Article  CAS  Google Scholar 

  • Kitajima TS, Hauf S, Ohsugi M, Yamamoto T, Watanabe Y . (2005). Human Bub1 defines the persistent cohesion site along the mitotic chromosome by affecting Shugoshin localization. Curr Biol 15: 353–359.

    Article  CAS  Google Scholar 

  • Kitajima TS, Kawashima SA, Watanabe Y . (2004). The conserved kinetochore protein shugoshin protects centromeric cohesion during meiosis. Nature 427: 510–517.

    Article  CAS  Google Scholar 

  • Kitajima TS, Sakuno T, Ishiguro K, Iemura S, Natsume T, Kawashima SA et al. (2006). Shugoshin collaborates with protein phosphatase 2A to protect cohesin. Nature 441: 46–52.

    Article  CAS  Google Scholar 

  • Kothe M, Kohls D, Low S, Coli R, Cheng AC, Jacques SL et al. (2007). Structure of the catalytic domain of human polo-like kinase 1. Biochemistry 46: 5960–5971.

    Article  CAS  Google Scholar 

  • Lee J, Kitajima TS, Tanno Y, Yoshida K, Morita T, Miyano T et al. (2008). Unified mode of centromeric protection by shugoshin in mammalian oocytes and somatic cells. Nat Cell Biol 10: 42–52.

    Article  CAS  Google Scholar 

  • Lengauer C, Kinzler KW, Vogelstein B . (1998). Genetic instabilities in human cancers. Nature 396: 643–649.

    Article  CAS  Google Scholar 

  • Losada A, Hirano M, Hirano T . (2002). Cohesin release is required for sister chromatid resolution, but not for condensin-mediated compaction, at the onset of mitosis. Genes Dev 16: 3004–3016.

    Article  CAS  Google Scholar 

  • Lupas A, Van Dyke M, Stock J . (1991). Predicting coiled coils from protein sequences. Science 252: 1162–1164.

    Article  CAS  Google Scholar 

  • Marston AL, Tham WH, Shah H, Amon A . (2004). A genome-wide screen identifies genes required for centromeric cohesion. Science 303: 1367–1370.

    Article  CAS  Google Scholar 

  • Mayr C, Bartel DP . (2009). Widespread shortening of 3′UTRs by alternative cleavage and polyadenylation activates oncogenes in cancer cells. Cell 138: 673–684.

    Article  CAS  Google Scholar 

  • McGuinness BE, Hirota T, Kudo NR, Peters JM, Nasmyth K . (2005). Shugoshin prevents dissociation of cohesin from centromeres during mitosis in vertebrate cells. PLoS Biol 3: e86.

    Article  Google Scholar 

  • Moore DP, Page AW, Tang TT, Kerrebrock AW, Orr-Weaver TL . (1998). The cohesion protein MEI-S332 localizes to condensed meiotic and mitotic centromeres until sister chromatids separate. J Cell Biol 140: 1003–1012.

    Article  CAS  Google Scholar 

  • Nasmyth K, Peters JM, Uhlmann F . (2000). Splitting the chromosome: cutting the ties that bind sister chromatids. Science 288: 1379–1385.

    Article  CAS  Google Scholar 

  • Peters JM . (2002). The anaphase-promoting complex: proteolysis in mitosis and beyond. Mol Cell 9: 931–943.

    Article  CAS  Google Scholar 

  • Pihan GA, Doxsey SJ . (1999). The mitotic machinery as a source of genetic instability in cancer. Semin Cancer Biol 9: 289–302.

    Article  CAS  Google Scholar 

  • Rabitsch KP, Gregan J, Schleiffer A, Javerzat JP, Eisenhaber F, Nasmyth K . (2004). Two fission yeast homologs of Drosophila Mei-S332 are required for chromosome segregation during meiosis I and II. Curr Biol 14: 287–301.

    Article  CAS  Google Scholar 

  • Rajagopalan H, Lengauer C . (2004). Aneuploidy and cancer. Nature 432: 338–341.

    Article  CAS  Google Scholar 

  • Reya T, Morrison SJ, Clarke MF, Weissman IL . (2001). Stem cells, cancer, and cancer stem cells. Nature 414: 105–111.

    Article  CAS  Google Scholar 

  • Riedel CG, Katis VL, Katou Y, Mori S, Itoh T, Helmhart W et al. (2006). Protein phosphatase 2A protects centromeric sister chromatid cohesion during meiosis I. Nature 441: 53–61.

    Article  CAS  Google Scholar 

  • Sakuno T, Tada K, Watanabe Y . (2009). Kinetochore geometry defined by cohesion within the centromere. Nature 458: 852–858.

    Article  CAS  Google Scholar 

  • Salic A, Waters JC, Mitchison TJ . (2004). Vertebrate shugoshin links sister centromere cohesion and kinetochore microtubule stability in mitosis. Cell 118: 567–578.

    Article  CAS  Google Scholar 

  • Shinmura K, Iwaizumi M, Igarashi H, Nagura K, Yamada H, Suzuki M et al. (2008). Induction of centrosome amplification and chromosome instability in p53-deficient lung cancer cells exposed to benzo[a]pyrene diol epoxide (B[a]PDE). J Pathol 216: 365–374.

    Article  CAS  Google Scholar 

  • Sumara I, Gimenez-Abian JF, Gerlich D, Hirota T, Kraft C, de la Torre C et al. (2004). Roles of polo-like kinase 1 in the assembly of functional mitotic spindles. Curr Biol 14: 1712–1722.

    Article  CAS  Google Scholar 

  • Sumara I, Vorlaufer E, Stukenberg PT, Kelm O, Redemann N, Nigg EA et al. (2002). The dissociation of cohesin from chromosomes in prophase is regulated by Polo-like kinase. Mol Cell 9: 515–525.

    Article  CAS  Google Scholar 

  • Suzuki H, Akiyama N, Tsuji M, Ohashi T, Saito S, Eto Y . (2006). Human Shugoshin mediates kinetochore-driven formation of kinetochore microtubules. Cell Cycle 5: 1094–1101.

    Article  CAS  Google Scholar 

  • Tang TT, Bickel SE, Young LM, Orr-Weaver TL . (1998). Maintenance of sister-chromatid cohesion at the centromere by the Drosophila MEI-S332 protein. Genes Dev 12: 3843–3856.

    Article  CAS  Google Scholar 

  • Tang Z, Shu H, Qi W, Mahmood NA, Mumby MC, Yu H . (2006). PP2A is required for centromeric localization of Sgo1 and proper chromosome segregation. Dev Cell 10: 575–585.

    Article  CAS  Google Scholar 

  • Tang Z, Sun Y, Harley SE, Zou H, Yu H . (2004). Human Bub1 protects centromeric sister-chromatid cohesion through Shugoshin during mitosis. Proc Natl Acad Sci USA 101: 18012–18017.

    Article  CAS  Google Scholar 

  • Waizenegger IC, Hauf S, Meinke A, Peters JM . (2000). Two distinct pathways remove mammalian cohesin from chromosome arms in prophase and from centromeres in anaphase. Cell 103: 399–410.

    Article  CAS  Google Scholar 

  • Wasch R, Robbins JA, Cross FR . (2010). The emerging role of APC/CCdh1 in controlling differentiation, genomic stability and tumor suppression. Oncogene 29: 1–10.

    Article  CAS  Google Scholar 

  • Xu Z, Cetin B, Anger M, Cho US, Helmhart W, Nasmyth K et al. (2009). Structure and function of the PP2A-shugoshin interaction. Mol Cell 35: 426–441.

    Article  CAS  Google Scholar 

  • Yamagishi Y, Sakuno T, Shimura M, Watanabe Y . (2008). Heterochromatin links to centromeric protection by recruiting shugoshin. Nature 455: 251–255.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Dr Suzuki of The Jikei University School of Medicine for providing the anti-hSgo1 antibody. This work was supported by a Grant-in-Aid for Scientific Research (C) (22590356) and for priority areas (20014007 and 221S0001) from the Japanese Ministry of Education, Culture, Sports, Science and Technology, Grants-in-Aid for the 3rd Term Comprehensive 10-Year-Strategy for Cancer Control and Grants-in-Aid for Cancer Research from the Japanese Ministry of Health (21-1) and from the Smoking Research Foundation.

Author information

Authors and Affiliations

  1. First Department of Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan

    T Kahyo, M Iwaizumi, K Shinmura, S Matsuura, H Yamada & H Sugimura

  2. First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan

    M Iwaizumi

  3. Second Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan

    S Matsuura

  4. Second Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, Japan

    T Nakamura

  5. Laboratory of Chromosome Dynamics, Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo, Japan

    Y Watanabe

Authors
  1. T Kahyo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Iwaizumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K Shinmura
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S Matsuura
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. T Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Y Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. H Yamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. H Sugimura
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to H Sugimura.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kahyo, T., Iwaizumi, M., Shinmura, K. et al. A novel tumor-derived SGOL1 variant causes abnormal mitosis and unstable chromatid cohesion. Oncogene 30, 4453–4463 (2011). https://doi.org/10.1038/onc.2011.152

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2011.152

Keywords

This article is cited by

Search

Advanced search

Quick links