Spindle Assembly Checkpoint review

The spindle assembly checkpoint (SAC), or mitotic checkpoint, is the main cell cycle control mechanism that governs mitosis. Incorrect spindle attachment causes the spindle assembly checkpoint to generate a wait anaphase signal that prevents the activation of the anaphase promoting complex (APC), an ubiquitin E3 ligase essential for progression of the cell cycle. Conserved components of the mammalian SAC include Bub1 (Cahill et al., 1998), BubR1 [Chan et al., 1998], Bub3 [Taylor et al.,ÿ1998], Mad1[Jin et al., 1998], Mad2 [Li and Benezra, 1996] and CENP-E [Weaver etÿal., 2003]. The checkpoint becomes activated as a result of spindle attachment errors [Rieder et al., 1995] or lack of tension on the mitotic spindle [Skoufias et al.,ÿ2001], which are caused by incorrect microtubule-kinetochore interactions.

Correct attachment is known as amphitelic or bi-oriented attachment where the kinetochore on each sister chromatid binds microtubules that emanate from opposite spindle poles. The mitotic spindle can bind the kinetochore incorrectly in three different ways: Monotelic attachment occurs when only one kinetochore is bound to microtubules from one spindle pole and the other kinetochore remains unattached. Syntelic attachment occurs when both kinetochores bind to microtubules that emanate from the same pole. Finally, merotelic attachment occurs when a single kinetochore binds microtubules from both spindle poles (Kelly and Funabiki, 2009). Defective attachment results in the inhibition of Cdc20 by checkpoint proteins Mad2, BubR1 and Bub3 through formation of a complex known as the mitotic checkpoint complex (MCC), which directly binds and inhibits the APC (Sudakin et al., 2001).

Kinetochore recruitment and activation of several essential spindle assembly checkpoint components such as BubR1, Mad2 and CENP-E is dependent on the kinase activity of Aurora B [Ditchfield et al., 2003]. Aurora B forms the enzymatic core of the chromosomal passenger complex (CPC), a group of highly conserved proteins, also including Inner Centromere Protein (INCENP), borealin and survivin (Vader et al., 2006). The CPC concentrates at the centromeres during prometaphase and isÿessential for kinetochore-microtubule interaction (Murata-Hori and Wang, 2002) and recruitment of spindle assembly checkpoint members during metaphase [Ditchfield et al., 2003].

In the ÿpresence of a kinetochore-spindle attachment error the SAC inhibits further progression of the cell cycle and the activity of Aurora B is required at the kinetochore to correct the errors present [Kelly and Funabiki, 2009; Lampson et al.,2004). In the absence of SAC activation Cdc20 binds to and activates the APC,which ubiquitinates securin and cyclin B and targets them for degradation by the 26S proteasome [Castro et al., 2005]. Destruction of securin activates the proteolytic enzyme sepharase, which cleaves cohesion allowing separation of sister chromatids [Hwang et al., 1998; Kim et al., 1998]. Once each kinetochore is correctly attached to the mitotic spindle, the checkpoint can be switched off. The exact mechanism by which the checkpoint signal is silenced is not fully understood although it is known that binding of microtubules to CENP-E results in the silencing of BubR1 kinase activity and reduced checkpoint activity [Mao et al., 2005]. Silencing of the checkpoint allows separation of sister chromatids and cell cycle progression.