Journal of the Formosan Medical Association
Volume 108, Issue 12 , Pages 904-911, December 2009

Suppression of Genomic Instabilities Caused by Chromosome Mis-segregation: A Perspective From Studying BubR1 and Sgo1

  • Wei Dai

      Affiliations

    • Corresponding Author InformationCorrespondence to: Dr Wei Dai, Department of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA

Department of Environmental Medicine and Pharmacology, New York University Langone Medical Center, Tuxedo, New York, USA

Received 20 August 2009; received in revised form 25 August 2009; accepted 4 November 2009.

Article Outline

Aneuploidy is a major manifestation of chromosomal instability, which is defined as a numerical abnormality of chromosomes in diploid cells. It is highly prevalent in a variety of human malignancies. Increased chromosomal instability is the major driving force for tumor development and progression. To suppress genomic stability during cell division, eukaryotic cells have evolved important molecular mechanisms, commonly referred to as checkpoints. The spindle checkpoint ensures that cells with defective mitotic spindles or a defective interaction between the spindles and kinetochores do not initiate chromosomal segregation during mitosis. Extensive studies have identified and characterized more than a dozen genes that play important roles in the regulation of the spindle checkpoint in mammalian cells. During the past decade, we have carried out extensive investigation of the role of BubR1 (Bub1-related kinase) and Sgo1 (shugoshin 1), two important gene products that safeguard accurate chromosome segregation during mitosis. This mini-review summarizes our studies, as well as those by other researchers in the field, on the functions of these two checkpoint proteins and their molecular regulation during mitosis. Further elucidation of the molecular mechanisms of the spindle checkpoint regulation has the potential to identify important mitotic targets for rational anticancer drug design.

Key Words:  BubR1 , chromosome mis-segregation , genomic instabilities , Sgo1

No full text is available. To read the body of this article, please view the PDF online.

 

Back to Article Outline

References 

  1. Gruber S , Haering CH , Nasmyth K . Chromosomal cohesin forms a ring . Cell . 2003;112:765–777
  2. Wang X , Dai W . Shugoshin, a guardian for sister chromatid segregation . Exp Cell Res . 2005;310:1–9
  3. Sumara I , Vorlaufer E , Stukenberg PT , et al.   The dissociation of cohesin from chromosomes in prophase is regulated by Polo-like kinase . Mol Cell . 2002;9:515–525
  4. Waizenegger IC , Hauf S , Meinke A , et al.   Two distinct pathways remove mammalian cohesin from chromosome arms in prophase and from centromeres in anaphase . Cell . 2000;103:399–410
  5. Hoyt MA , Totis L , Roberts BT . S. cerevisiae genes required for cell cycle arrest in response to loss of microtubule function . Cell . 1991;66:507–517
  6. Li R , Murray AW . Feedback control of mitosis in budding yeast . Cell . 1991;66:519–531
  7. Weiss E , Winey M . The Saccharomyces cerevisiae spindle pole body duplication gene MPS1 is part of a mitotic checkpoint . J Cell Biol . 1996;132:111–123
  8. Cahill DP , Lengauer C , Yu J , et al.   Mutations of mitotic checkpoint genes in human cancers . Nature . 1998;392:300–303
  9. Chan GK , Schaar BT , Yen TJ . Characterization of the kinetochore binding domain of CENP-E reveals interactions with the kinetochore proteins CENP-F and hBUBR1 . J Cell Biol . 1998;143:49–63
  10. Li W , Lan Z , Wu H , et al.   BUBR1 phosphorylation is regulated during mitotic checkpoint activation . Cell Growth Differ . 1999;10:769–775
  11. Ouyang B , Lan Z , Meadows J , et al.   Human Bub1: a putative spindle checkpoint kinase closely linked to cell proliferation . Cell Growth Differ . 1998;9:877–885
  12. Hoffman DB , Pearson CG , Yen TJ , et al.   Microtubule-dependent changes in assembly of microtubule motor proteins and mitotic spindle checkpoint proteins at PtK1 kinetochores . Mol Biol Cell . 2001;12:1995–2009
  13. Chan GK , Jablonski SA , Sudakin V , et al.   Human BUBR1 is a mitotic checkpoint kinase that monitors CENP-E functions at kinetochores and binds the cyclosome/APC . J Cell Biol . 1999;146:941–954
  14. Chi YH , Haller K , Ward MD , et al.   Requirements for protein phosphorylation and the kinase activity of polo-like kinase 1 (Plk1) for the kinetochore function of mitotic arrest deficiency protein 1 (Mad1) . J Biol Chem . 2008;283:35834–35844
  15. Wu H , Lan Z , Li W , et al.   p55CDC/hCDC20 is associated with BUBR1 and may be a downstream target of the spindle checkpoint kinase . Oncogene . 2000;19:4557–4562
  16. Yu H . Regulation of APC-Cdc20 by the spindle checkpoint . Curr Opin Cell Biol . 2002;14:706–714
  17. Yu H . Cdc20: a WD40 activator for a cell cycle degradation machine . Mol Cell . 2007;27:3–16
  18. Choi E , Choe H , Min J , et al.   BubR1 acetylation at prometaphase is required for modulating APC/C activity and timing of mitosis . EMBO J . 2009;28:2077–2089
  19. Dai W , Wang Q , Liu T , et al.   Slippage of mitotic arrest and enhanced tumor development in mice with BubR1 haploinsufficiency . Cancer Res . 2004;64:440–445
  20. Rao CV , Yang YM , Swamy MV , et al.   Colonic tumorigenesis in BubR1+/–Apc–/+ compound mutant mice is linked to premature separation of sister chromatids and enhanced genomic instability . Proc Natl Acad Sci USA . 2005;102:4365–4370
  21. Baker DJ , Jeganathan KB , Cameron JD , et al.   BubR1 insufficiency causes early onset of aging-associated pheno-types and infertility in mice . Nat Genet . 2004;36:744–749
  22. Wang Q , Liu T , Fang Y , et al.   BUBR1 deficiency results in abnormal megakaryopoiesis . Blood . 2004;103:1278–1285
  23. Iwanaga Y , Chi YH , Miyazato A , et al.   Heterozygous deletion of mitotic arrest-deficient protein 1 (MAD1) increases the incidence of tumors in mice . Cancer Res . 2007;67:160–166
  24. Michel LS , Liberal V , Chatterjee A , et al.   MAD2 haploinsufficiency causes premature anaphase and chromo-some instability in mammalian cells . Nature . 2001;409:355–359
  25. Hanks S , Coleman K , Reid S , et al.   Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B . Nat Genet . 2004;36:1159–1161
  26. Duan Q , Komissarova E , Dai W . Arsenic trioxide suppresses paclitaxel-induced mitotic arrest . Cell Prolif . 2009;42:404–411
  27. Indjeian VB , Stern BM , Murray AW . The centromeric protein Sgo1 is required to sense lack of tension on mitotic chromosomes . Science . 2005;307:130–133
  28. Kitajima TS , Kawashima SA , Watanabe Y . The conserved kinetochore protein shugoshin protects centromeric cohesion during meiosis . Nature . 2004;427:510–517
  29. Marston AL , Tham WH , Shah H , et al.   A genome-wide screen identifies genes required for centromeric cohesion . Science . 2004;303:1367–1370
  30. Davis BK . Genetic analysis of a meiotic mutant resulting in precocious sister-centromere separation in Drosophila melanogaster . Mol Gen Genet . 1971;113:251–272
  31. Kerrebrock AW , Moore DP , Wu JS , et al.   Mei-S332, a Drosophila protein required for sister-chromatid cohesion, can localize to meiotic centromere regions . Cell . 1995;83:247–256
  32. Tang TT , Bickel SE , Young LM , et al.   Maintenance of sister-chromatid cohesion at the centromere by the Drosophila MEI-S332 protein . Genes Dev . 1998;12:3843–3856
  33. Goldstein LS . Mechanisms of chromosome orientation revealed by two meiotic mutants in Drosophila melanogaster . Chromosoma . 1980;78:79–111
  34. Lee JY , Dej KJ , Lopez JM , et al.   Control of centromere localization of the MEI-S332 cohesion protection protein . Curr Biol . 2004;14:1277–1283
  35. Salic A , Waters JC , Mitchison TJ . Vertebrate shugoshin links sister centromere cohesion and kinetochore micro-tubule stability in mitosis . Cell . 2004;118:567–578
  36. McGuinness BE , Hirota T , Kudo NR , et al.   Shugoshin prevents dissociation of cohesin from centromeres during mitosis in vertebrate cells . PLoS Biol . 2005;3:e86
  37. Wang X , Yang Y , Dai W . Differential subcellular localizations of two human Sgo1 isoforms: implications in regulation of sister chromatid cohesion and microtubule dynamics . Cell Cycle . 2006;5:635–640
  38. Wang X , Yang Y , Duan Q , et al.   sSgo1, a major splice variant of Sgo1, functions in centriole cohesion where it is regulated by Plk1 . Dev Cell . 2008;14:331–341
  39. Tang Z , Sun Y , Harley SE , et al.   Human Bub1 protects centromeric sister-chromatid cohesion through Shugoshin during mitosis . Proc Natl Acad Sci USA . 2004;101:18012–18017
  40. Katis VL , Matos J , Mori S , et al.   Spo13 facilitates monopolin recruitment to kinetochores and regulates maintenance of centromeric cohesion during yeast meiosis . Curr Biol . 2004;14:2183–2196
  41. Rabitsch KP , Gregan J , Schleiffer AJ , et al.   Two fission yeast homologs of Drosophila Mei-S332 are required for chromosome segregation during meiosis I and II . Curr Biol . 2004;14:287–301
  42. Kitajima TS , Hauf S , Ohsugi M , et al.   Human Bub1 defines the persistent cohesion site along the mitotic chromosome by affecting Shugoshin localization . Curr Biol . 2005;15:353–359
  43. Yang Y , Wang X , Dai W . Human Sgo1 is an excellent target for induction of apoptosis of transformed cells . Cell Cycle . 2006;5:896–901
  44. Clarke AS , Tang TT , Ooi DL , et al.   POLO kinase regulates the Drosophila centromere cohesion protein MEI-S332 . Dev Cell . 2005;8:53–64
  45. Kitajima TS , Sakuno T , Ishiguro K , et al.   Shugoshin collaborates with protein phosphatase 2A to protect cohesin . Nature . 2006;441:46–52
  46. Riedel CG , Katis VL , Katou Y , et al.   Protein phosphatase 2A protects centromeric sister chromatid cohesion during meiosis I . Nature . 2006;441:53–61
  47. Tang Z , Shu H , Qi W , et al.   PP2A is required for centromeric localization of Sgo1 and proper chromosome segregation . Dev Cell . 2006;10:575–585
  48. Dai W , Wang X . The Yin and Yang of centromeric cohesion of sister chromatids: mitotic kinases meet protein phosphatase 2A . Cell Div . 2006;1:9

PII: S0929-6646(10)60002-2

doi:10.1016/S0929-6646(10)60002-2

Journal of the Formosan Medical Association
Volume 108, Issue 12 , Pages 904-911, December 2009

Article Tools