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The Spindle Assembly Checkpoint Mechanism and the Consequences of its Dysfunction

The Spindle Assembly Checkpoint Mechanism and the Consequences of its Dysfunction

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Published by Jonathan McLatchie
Reviews the elegant design of the mitotic spindle assembly checkpoint pathway, the molecular processes that minimize the risks of improper chromosome segregation during cell division as a consequence of improper microtubule-kinetochore attachment.
Reviews the elegant design of the mitotic spindle assembly checkpoint pathway, the molecular processes that minimize the risks of improper chromosome segregation during cell division as a consequence of improper microtubule-kinetochore attachment.

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Published by: Jonathan McLatchie on Dec 10, 2013
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07/11/2014

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The Spindle Assembly Checkpoint Mechanism and the Consequences of its Dysfunction
 Jonathan McLatchie (B.Sc, M.Res) November 2013
 
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Introduction
Mitotic division (“M phase”) is the culmination of the eukaryotic cell cycle for somatic cells.
Mitotic cell division is divided into six phases. The first is prophase, which is characterized by chromosome condensation (the reorganization of the sister chromatids into compact rod-like structures). Following condensation, assembly of the mitotic spindle apparatus occurs outside the nucleus between the two centrosomes which have duplicated and moved apart to the poles of the cell. The second stage of mitosis is prometaphase, which is marked by the disintegration of the nuclear envelope. This is followed by metaphase, where sister chromatids are attached to opposite spindle poles by microtubules bound to protein complexes called kinetochores. In animal cells, 10-40 microtubule-binding sites are associated with any one kinetochore. In yeast, each kinetochore contains only one attachment site. At this point, the chromosomes are seen to be aligned at the cell
’s equator (the metaphase plate).
 The sister chromatids are themselves held together by the protein cohesin. At anaphase, the sister chromatids separate to form two daughter chromosomes that are pulled towards opposite poles of the spindle. Microtubules bound to kinetochores, as well
as the centrosome, are reeled in towards the cell’s periphery by specialized dynein motor
proteins
that ‘walk’ towards the minus end of the microtubule but are held stationary by
cargo-binding domains that are anchored to the cell cortex. The next phase in the cycle is telophase, the stage at which the daughter chromosomes de-condense at the spindle poles and a new nuclear envelope is assembled. A contractile ring is then formed, marking the final stage of the process -- cytokinesis. The contractile ring is comprised of actin and myosin filaments. The cell thus differentiates to form two new daughter cells, each with a nucleus containing a complete and identical set of chromosomes. The consequences of improper attachment can be catastrophic, with segregation of two chromosome copies to a single daughter cell. The spindle assembly checkpoint pathway is responsible for inhibiting progression of mitosis from metaphase to anaphase until each of
 
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the sister chromatids has become correctly bi-oriented and securely associated with the mitotic spindle. Progression from metaphase to anaphase is mediated by the anaphase promoting complex (APC), an E3 ubiquitin ligase. When bound to a protein, Cdc20, the APC functions to ubiquitinate securin (a protein that prevents the cleavage of cohesin by the enzyme separase), as well as the S and M cyclins, thereby targeting them for destruction (1-2). The APC is phosphorylated by cyclin dependent kinases (Cdks), thus rendering it able to bind to Cdc20 and form the APC
Cdc20
complex. The APC
Cdc20
 complex is autoinhibitory, since destruction of Cdks results in a decreased rate of APC phosphorylation and, as a consequence, binding of Cdc20. Microtubule attachment to kinetochores during prometaphase is governed by a stochastic
“search and capture”
 mechanism (3-5). The property of dynamic instability facilitates the
process by which microtubules ‘search’ for kinetochore attachment sites. When a microtubule encounters a kinetochore, the kinetochore is ‘captured’ by means of side
-on attachment. The sister chromatids are subsequently positioned at one of the poles of the cell, where more microtubules become attached. After the kinetochore becomes associated with a microtubule from the other pole, the chromosomes move to the equator. This checkpoint pathway relies on a specialized mechanism for monitoring the security of kinetochore-microtubule attachment (6). In the case of improper attachment, the kinetochore sends out a signal
 –
 the wait anaphase signal
 –
 that inhibits activation of APC
Cdc20
, thereby arresting metaphase-to-anaphase progression. The purpose of this paper is to review the elegant molecular mechanisms that underlie the spindle assembly checkpoint and discuss the implications of its dysfunction.
Monitoring Spindle-Kinetochore Attachment
The precise mechanism by which the spindle checkpoint system detects improper chromatid bi-orientation has not been fully elucidated. Two main hypotheses have been proposed, each with its own supporting data (7). One proposal suggests that the system monitors the

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