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The spindle checkpoint blocks the entry of a cell undergoing mitosis into anaphase until all chromosomes are properly attached to the meiotic or mitotic spindle. To achieve proper segregation, the two kinetochores on the sister chromatids must be attached to opposite spindle poles. Only this pattern of attachment will ensure that each daughter cell receives one copy of the chromosome.

Overview

The spindle checkpoint is an active signal produced by improperly attached kinetochores, which is conserved in all eukaryotes. It includes MAD (mitotic arrest deficient) and BUB (budding uninhibited by benzimidazole) proteins. [1] Cell cycle arrest protein BUB3 triggers the spindle checkpoint of the cell to unattached kinetochores. BUB3 together with Mad2,MAD3, and Cdc20 forms an inhibitory complex at the kinetochore, called the Mitotic checkpoint complex, preventing the progression of mitosis. BUB3 binds to Mad3 and BUB1B through the short linear motif known as the GLEBS motif. The exact order of attachements which must take place in order to form the mitotic checkpoint complex remains unknown. It is possible that Mad2/Cdc20 form a complex at the same time as BUBR1/BUB3/Cdc20 form another complex, and these two subcomplexes are consequently combined to form the mitotic checkpoint complex. [1] When sister kinetochores are properly attached to opposite spindle poles, forces in the mitotic spindle generate tension at the kinetochores. Kinetochores that are attached to the mitotic spindle but that are not under tension also trigger the spindle checkpoint. Unattached kinetochores maintain the spindle checkpoint, and it is known that all of the spindle checkpoint proteins localize to the kinetochores in prometaphase. [1] Upon microtubule-kinetochore attachment, a mechanism of stripping, using the motor activity of a dynein-dynein complex transports spindle checkpoint proteins away from the kinetochores. [2] The mechanism by which kinetochores detect attachment and tension is unclear.

The spindle checkpoint blocks anaphase entry by inhibiting the anaphase-promoting complex. The inhibition of the APC is achieved through direct interaction between MAD2 and the APC activator Cdc20. In order to sequester the Cdc20, Mad2 must be recruited to the kinetochores. To do this, Mad1 recruits the open conformer of Mad2 (O-Mad2) to the kinetochores. This O-Mad2 changes its confirmation to closed Mad2 (C-Mad2) and binds Mad1. This Mad1/C-Mad2 complex is responsible for the recruitment of more O-Mad2 to the kinetochores, which changes its confirmation to C-Mad2 and binds Cdc20. This sequesteration of Cdc20 is essential for maintaining the spindle checkpoint. [1] During normal anaphase of the cell cycle, APC containing Cdc20 becomes activated. When this happens the Cdc20 directs the enzyme complex to ubiquitinate the anaphase inhibitor securin. The ubiquitination and destruction of securin at the end of metaphase releases the active protease called separase. Separase cleaves the cohesion molecules that hold the sister chromatids together to activate anaphase. When the kinetochores do not receive spindle fibers from both poles of the cell, Mad2 binds to Cdc20 and does not allow the APC to bind to the Cdc20 and consequently allow the ubiquitination of securin. As a result, the centromeres receive the signal and extend more chromosomal spindle fibers until the kinetochores are attached. When this happens the Mad2 protein complex releases Cdc20 and allows APC to bind to it and initiate the ubiquitination of securin to continue into anaphase. [3]

At the same time that MAD2 is sequestering Cdc20, the centromere protein (CENP)-E activates BUBR1, which blocks also blocks anaphase. [2] The localization of MAD2 and BubR1 to the kinetochore may be dependent on the Aurora B kinase.[4] Cells lacking Aurora B fail to arrest in metaphase even when chromosomes lack microtubule attachment.[5]

When the spindle checkpoint misfuctions, this can lead to chromosome missegregation, aneuploidy and even tumorogenesis. [2]

References

  1. ^ a b c d "The Mad1/Mad2 complex as a template for Mad2 activation in the spindle assembly checkpoint." Current Biology 15 (2005): 214-25. Elsevier Ltd. Web. <http://web.me.com/skotheim/Site/Cell_Cycle_Course_files/Antoni_Musacchio2005.pdf>
  2. ^ a b c Musacchio, Andrea, and Edward Salmon. "The spindle-assembly checkpoint in time and space." Nature Reviews Molecular Cell Biology 8: 379-93. Nature. 1 May 2007. Web. 26 Nov. 2009. <http://www.nature.com/nrm/journal/v8/n5/full/nrm2163.html>.
  3. ^ Morgan, David O. The Cell Cycle: Principles of Control. London: New Science Ltd, 2007. Print.
  4. ^ S.M. Lens, R.M. Wolthuis, R. Klompmaker, J. Kauw, R. Agami, T. Brummelkamp, G. Kops and R.H. Medema, Survivin is required for a sustained spindle checkpoint arrest in response to lack of tension, EMBO J. 22 (2003), pp. 2934–2947.
  5. ^ S. Hauf, R.W. Cole, S. LaTerra, C. Zimmer, G. Schnapp, R. Walter, A. Heckel, J. vanMeel, C.L. Rieder and J.M. Peters, The small molecule Hesperadin reveals a role for Aurora B in correcting kinetochore–microtubule attachment and in maintaining the spindle assembly checkpoint, J. Cell Biol. 161 (2003), pp. 281–294.

http://www.uniprot.org/uniprot/O60566

http://www.pnas.org/content/104/4/1201

http://www.jbc.org/cgi/content/abstract/276/28/26559

http://www.sciencemag.org/cgi/content/abstract/326/5955/991

http://www.nature.com/ncb/journal/v1/n8/abs/ncb1299_514.html

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