Editing Spindle checkpoint (section)

=== Checkpoint activation ===

The SAC monitors the interaction between improperly connected kinetochores and spindle [[microtubules]], and is maintained until kinetochores are properly attached to the spindle. During [[prometaphase]], CDC20 and the SAC proteins concentrate at the kinetochores before attachment to the spindle assembly. These proteins keep the SAC activated until they are removed and the correct kinetochore-microtubule attachment is made. Even a single unattached kinetochore can maintain the spindle checkpoint.<ref name="Mad2"/> After attachment of microtubule plus-ends and formation of kinetochore microtubules, MAD1 and MAD2 are depleted from the kinetochore assembly. Another regulator of checkpoint activation is kinetochore tension. When sister kinetochores are properly attached to opposite spindle poles, forces in the mitotic spindle generate tension at the kinetochores. Bi-oriented sister kinetochores stabilize the kinetochore-microtubule assembly whereas weak tension has a destabilizing effect. In response to incorrect kinetochore attachments such as [[Kinetochore#Verification of kinetochore-MT anchoring|syntelic]] attachment, where both kinetochores becomes attached to one spindle pole, the weak tension generated destabilizes the incorrect attachment and allows the kinetochore to reattach correctly to the spindle body. During this process, kinetochores that are attached to the mitotic spindle but that are not under tension trigger the spindle checkpoint. Aurora-B/Ipl1 kinase of the [[chromosomal passenger complex]] functions as the tensions sensor in improper kinetochore attachments. It detects and destabilizes incorrect attachments through control of the microtubule-severing KINI kinesin MCAK, the [[DASH complex]], and the [[NDC80|Ndc80/Hec1]] complex<ref name="MartinLluesma2002">{{cite journal | vauthors = Martin-Lluesma S, Stucke VM, Nigg EA | title = Role of Hec1 in spindle checkpoint signaling and kinetochore recruitment of Mad1/Mad2 | journal = Science | volume = 297 | issue = 5590 | pages = 2267–70 | date = September 2002 | pmid = 12351790 | doi = 10.1126/science.1075596 | bibcode = 2002Sci...297.2267M | s2cid = 7879023 }}</ref>  at the microtubule-kinetochore interface.<ref name="Nature"/> The Aurora-B/Ipl1 kinase is also critical in correcting [[Kinetochore#Verification of kinetochore-MT anchoring|merotelic]] attachments, where one kinetochore is simultaneously attached to both spindle poles. Merotelic attachments generate sufficient tension and are not detected by the SAC, and without correction, may result in chromosome mis-segregation due to slow chromatid migration speed. While microtubule attachment is independently required for SAC activation, it is unclear whether tension is an independent regulator of SAC, although it is clear that differing regulatory behaviors arise with tension.

Once activated, the spindle checkpoint blocks [[anaphase]] entry by inhibiting the [[anaphase-promoting complex]] via regulation of the activity of mitotic checkpoint complex. The mechanism of inhibition of APC by the mitotic checkpoint complex is poorly understood, although it is hypothesized that the MCC binds to APC as a [[pseudosubstrate]] using the [[KEN-box]] motif in [[BUBR1]]. At the same time that mitotic checkpoint complex is being activated, the [[centromere]] protein [[CENPE|CENP-E]] activates BUBR1, which also blocks anaphase.<ref name="Nature"/>