全部 标题 作者
关键词 摘要

OALib Journal期刊
ISSN: 2333-9721
费用:99美元

查看量下载量

相关文章

更多...
PLOS ONE  2009 

Reverse Engineering of the Spindle Assembly Checkpoint

DOI: 10.1371/journal.pone.0006495

Full-Text   Cite this paper   Add to My Lib

Abstract:

The Spindle Assembly Checkpoint (SAC) is an intracellular mechanism that ensures proper chromosome segregation. By inhibiting Cdc20, a co-factor of the Anaphase Promoting Complex (APC), the checkpoint arrests the cell cycle until all chromosomes are properly attached to the mitotic spindle. Inhibition of Cdc20 is mediated by a conserved network of interacting proteins. The individual functions of these proteins are well characterized, but understanding of their integrated function is still rudimentary. We here describe our attempts to reverse-engineer the SAC network based on gene deletion phenotypes. We begun by formulating a general model of the SAC which enables us to predict the rate of chromosomal missegregation for any putative set of interactions between the SAC proteins. Next the missegregation rates of seven yeast strains are measured in response to the deletion of one or two checkpoint proteins. Finally, we searched for the set of interactions that correctly predicted the observed missegregation rates of all deletion mutants. Remarkably, although based on only seven phenotypes, the consistent network we obtained successfully reproduces many of the known properties of the SAC. Further insights provided by our analysis are discussed.

References

[1]  Homer HA, McDougall A, Levasseur M, Yallop K, Murdoch AP, et al. (2005) Mad2 prevents aneuploidy and premature proteolysis of cyclin B and securin during meiosis I in mouse oocytes. Genes Dev 19: 202–207.
[2]  Shonn MA, McCarroll R, Murray AW (2000) Requirement of the spindle checkpoint for proper chromosome segregation in budding yeast meiosis. Science 289: 300–303.
[3]  Rajagopalan H, Lengauer C (2004) Aneuploidy and cancer. Nature 432: 338–341.
[4]  Kops GJ, Weaver BA, Cleveland DW (2005) On the road to cancer: aneuploidy and the mitotic checkpoint. Nat Rev Cancer 5: 773–785.
[5]  Westermann S, Drubin DG, Barnes G (2007) Structures and functions of yeast kinetochore complexes. Annu Rev Biochem 76: 563–591.
[6]  McAinsh AD, Tytell JD, Sorger PK (2003) Structure, function, and regulation of budding yeast kinetochores. Annu Rev Cell Dev Biol 19: 519–539.
[7]  Musacchio A, Salmon ED (2007) The spindle-assembly checkpoint in space and time. Nat Rev Mol Cell Biol 8: 379–393.
[8]  Cleveland DW, Mao Y, Sullivan KF (2003) Centromeres and kinetochores: from epigenetics to mitotic checkpoint signaling. Cell 112: 407–421.
[9]  Lew DJ, Burke DJ (2003) The spindle assembly and spindle position checkpoints. Annu Rev Genet 37: 251–282.
[10]  Ruchaud S, Carmena M, Earnshaw WC (2007) Chromosomal passengers: conducting cell division. Nat Rev Mol Cell Biol 8: 798–812.
[11]  Hwang LH, Lau LF, Smith DL, Mistrot CA, Hardwick KG, et al. (1998) Budding yeast Cdc20: a target of the spindle checkpoint. Science 279: 1041–1044.
[12]  Peters JM (2006) The anaphase promoting complex/cyclosome: a machine designed to destroy. Nat Rev Mol Cell Biol 7: 644–656.
[13]  Visintin R, Prinz S, Amon A (1997) CDC20 and CDH1: a family of substrate-specific activators of APC-dependent proteolysis. Science 278: 460–463.
[14]  Uhlmann F, Lottspeich F, Nasmyth K (1999) Sister-chromatid separation at anaphase onset is promoted by cleavage of the cohesin subunit Scc1. Nature 400: 37–42.
[15]  Haering CH, Farcas AM, Arumugam P, Metson J, Nasmyth K (2008) The cohesin ring concatenates sister DNA molecules. Nature 454: 297–301.
[16]  Li R, Murray AW (1991) Feedback control of mitosis in budding yeast. Cell 66: 519–531.
[17]  Hoyt MA, Totis L, Roberts BT (1991) S. cerevisiae genes required for cell cycle arrest in response to loss of microtubule function. Cell 66: 507–517.
[18]  Weiss E, Winey M (1996) The Saccharomyces cerevisiae spindle pole body duplication gene MPS1 is part of a mitotic checkpoint. J Cell Biol 132: 111–123.
[19]  Hardwick KG, Weiss E, Luca FC, Winey M, Murray AW (1996) Activation of the budding yeast spindle assembly checkpoint without mitotic spindle disruption. Science 273: 953–956.
[20]  Chan CS, Botstein D (1993) Isolation and characterization of chromosome-gain and increase-in-ploidy mutants in yeast. Genetics 135: 677–691.
[21]  De Antoni A, Pearson CG, Cimini D, Canman JC, Sala V, et al. (2005) The Mad1/Mad2 complex as a template for Mad2 activation in the spindle assembly checkpoint. Curr Biol 15: 214–225.
[22]  Pan J, Chen RH (2004) Spindle checkpoint regulates Cdc20p stability in Saccharomyces cerevisiae. Genes Dev 18: 1439–1451.
[23]  Sudakin V, Chan GK, Yen TJ (2001) Checkpoint inhibition of the APC/C in HeLa cells is mediated by a complex of BUBR1, BUB3, CDC20, and MAD2. J Cell Biol 154: 925–936.
[24]  Hardwick KG, Johnston RC, Smith DL, Murray AW (2000) MAD3 encodes a novel component of the spindle checkpoint which interacts with Bub3p, Cdc20p, and Mad2p. J Cell Biol 148: 871–882.
[25]  Holt LJ, Krutchinsky AN, Morgan DO (2008) Positive feedback sharpens the anaphase switch. Nature.
[26]  Tang Z, Shu H, Oncel D, Chen S, Yu H (2004) Phosphorylation of Cdc20 by Bub1 provides a catalytic mechanism for APC/C inhibition by the spindle checkpoint. Mol Cell 16: 387–397.
[27]  Chung E, Chen RH (2003) Phosphorylation of Cdc20 is required for its inhibition by the spindle checkpoint. Nat Cell Biol 5: 748–753.
[28]  Doncic A, Ben-Jacob E, Barkai N (2006) Noise resistance in the spindle assembly checkpoint. Mol Syst Biol 2: 2006 0027.
[29]  Doncic A, Ben-Jacob E, Barkai N (2005) Evaluating putative mechanisms of the mitotic spindle checkpoint. Proc Natl Acad Sci U S A 102: 6332–6337.
[30]  Sear RP, Howard M (2006) Modeling dual pathways for the metazoan spindle assembly checkpoint. Proc Natl Acad Sci U S A 103: 16758–16763.
[31]  Mistry HB, MacCallum DE, Jackson RC, Chaplain MA, Davidson FA (2008) Modeling the temporal evolution of the spindle assembly checkpoint and role of Aurora B kinase. Proc Natl Acad Sci U S A 105: 20215–20220.
[32]  Ibrahim B, Diekmann S, Schmitt E, Dittrich P (2008) In-silico modeling of the mitotic spindle assembly checkpoint. PLoS ONE 3: e1555.
[33]  Ibrahim B, Dittrich P, Diekmann S, Schmitt E (2008) Mad2 binding is not sufficient for complete Cdc20 sequestering in mitotic transition control (an in silico study). Biophys Chem 134: 93–100.
[34]  Simonetta M, Manzoni R, Mosca R, Mapelli M, Massimiliano L, et al. (2009) The influence of catalysis on mad2 activation dynamics. PLoS Biol 7: e10.
[35]  Yuen KW, Warren CD, Chen O, Kwok T, Hieter P, et al. (2007) Systematic genome instability screens in yeast and their potential relevance to cancer. Proc Natl Acad Sci U S A 104: 3925–3930.
[36]  Warren CD, Brady DM, Johnston RC, Hanna JS, Hardwick KG, et al. (2002) Distinct chromosome segregation roles for spindle checkpoint proteins. Mol Biol Cell 13: 3029–3041.
[37]  Hieter P, Mann C, Snyder M, Davis RW (1985) Mitotic stability of yeast chromosomes: a colony color assay that measures nondisjunction and chromosome loss. Cell 40: 381–392.
[38]  Kerscher O, Crotti LB, Basrai MA (2003) Recognizing chromosomes in trouble: association of the spindle checkpoint protein Bub3p with altered kinetochores and a unique defective centromere. Mol Cell Biol 23: 6406–6418.
[39]  Millband DN, Hardwick KG (2002) Fission yeast Mad3p is required for Mad2p to inhibit the anaphase-promoting complex and localizes to kinetochores in a Bub1p-, Bub3p-, and Mph1p-dependent manner. Mol Cell Biol 22: 2728–2742.
[40]  Howell BJ, Moree B, Farrar EM, Stewart S, Fang G, et al. (2004) Spindle checkpoint protein dynamics at kinetochores in living cells. Curr Biol 14: 953–964.
[41]  Farr KA, Hoyt MA (1998) Bub1p kinase activates the Saccharomyces cerevisiae spindle assembly checkpoint. Mol Cell Biol 18: 2738–2747.
[42]  Vigneron S, Prieto S, Bernis C, Labbe JC, Castro A, et al. (2004) Kinetochore localization of spindle checkpoint proteins: who controls whom? Mol Biol Cell 15: 4584–4596.
[43]  Gillett ES, Espelin CW, Sorger PK (2004) Spindle checkpoint proteins and chromosome-microtubule attachment in budding yeast. J Cell Biol 164: 535–546.
[44]  King EM, Rachidi N, Morrice N, Hardwick KG, Stark MJ (2007) Ipl1p-dependent phosphorylation of Mad3p is required for the spindle checkpoint response to lack of tension at kinetochores. Genes Dev 21: 1163–1168.
[45]  Hardwick KG, Murray AW (1995) Mad1p, a phosphoprotein component of the spindle assembly checkpoint in budding yeast. J Cell Biol 131: 709–720.
[46]  Burke DJ, Stukenberg PT (2008) Linking kinetochore-microtubule binding to the spindle checkpoint. Dev Cell 14: 474–479.
[47]  Burton JL, Solomon MJ (2007) Mad3p, a pseudosubstrate inhibitor of APCCdc20 in the spindle assembly checkpoint. Genes Dev 21: 655–667.
[48]  Nilsson J, Yekezare M, Minshull J, Pines J (2008) The APC/C maintains the spindle assembly checkpoint by targeting Cdc20 for destruction. Nat Cell Biol 10: 1411–1420.
[49]  Fraschini R, Beretta A, Sironi L, Musacchio A, Lucchini G, et al. (2001) Bub3 interaction with Mad2, Mad3 and Cdc20 is mediated by WD40 repeats and does not require intact kinetochores. Embo J 20: 6648–6659.
[50]  Poddar A, Stukenberg PT, Burke DJ (2005) Two complexes of spindle checkpoint proteins containing Cdc20 and Mad2 assemble during mitosis independently of the kinetochore in Saccharomyces cerevisiae. Eukaryot Cell 4: 867–878.
[51]  Larsen NA, Al-Bassam J, Wei RR, Harrison SC (2007) Structural analysis of Bub3 interactions in the mitotic spindle checkpoint. Proc Natl Acad Sci U S A 104: 1201–1206.
[52]  King EM, van der Sar SJ, Hardwick KG (2007) Mad3 KEN boxes mediate both Cdc20 and Mad3 turnover, and are critical for the spindle checkpoint. PLoS ONE 2: e342.

Full-Text

Contact Us

service@oalib.com

QQ:3279437679

WhatsApp +8615387084133