Editing Spindle checkpoint (section)

=== Other genes not traditionally associated with the SAC in cancer ===

Clearly variations in the physiological levels of these proteins (such as Mad2 or BubR1) are associated with aneuploidy and tumorigenesis, and this has been demonstrated using  [[animal model]]s.<ref name="Sotillo2007">{{cite journal | vauthors = Sotillo R, Hernando E, Díaz-Rodríguez E, Teruya-Feldstein J, Cordón-Cardo C, Lowe SW, Benezra R | title = Mad2 overexpression promotes aneuploidy and tumorigenesis in mice | journal = Cancer Cell | volume = 11 | issue = 1 | pages = 9–23 | date = January 2007 | pmid = 17189715 | pmc = 1850996 | doi = 10.1016/j.ccr.2006.10.019 }}</ref><ref name="yamamoto2007">{{cite journal | vauthors = Yamamoto Y, Matsuyama H, Chochi Y, Okuda M, Kawauchi S, Inoue R, Furuya T, Oga A, Naito K, Sasaki K | title = Overexpression of BUBR1 is associated with chromosomal instability in bladder cancer | journal = Cancer Genetics and Cytogenetics | volume = 174 | issue = 1 | pages = 42–7 | date = April 2007 | pmid = 17350465 | doi = 10.1016/j.cancergencyto.2006.11.012 }}</ref> However, recent studies indicate that what seems to happen is a more complicated scenario: aneuploidy would drive a high incidence of tumorigenesis only when alterations in the levels of specific mitotic checkpoint components (either reduction or overexpression) in tissues is also inducing other defects able to predispose them to tumors.<ref name="weaver2009">{{cite journal | vauthors = Weaver BA, Cleveland DW | title = The role of aneuploidy in promoting and suppressing tumors | journal = The Journal of Cell Biology | volume = 185 | issue = 6 | pages = 935–7 | date = June 2009 | pmid = 19528293 | pmc = 2711620 | doi = 10.1083/jcb.200905098 }}</ref>
That is, defects such as an increase in DNA damage, chromosomal rearrangements, and/or a decreased incidence of cell death. For some mitotic checkpoint components, it is known that they are implicated in functions outside mitosis: nuclear import (Mad1), transcriptional repression (Bub3), and cell death, DNA damage response, aging, and [[megakaryopoiesis]] for BubR1. All this supports the conclusion that increase in tumorigenesis is associated with defects other than aneuploidy alone.<ref name="weaver2009"/>

Cancer-associated mutations affecting known checkpoint genes like BUB1 or BUBR1 are actually rare. However, several proteins implicated in cancer have intersections to spindle assembly networks. Key tumor suppressors such as [[p53]] also play a role in the spindle checkpoint. Absence of p53, the most commonly mutated gene in human cancer, has a major effect on cell cycle checkpoint regulators and has been shown to act at the G1 checkpoint in the past, but now appears to be important in regulating the spindle checkpoint as well.<ref name="Cross1995">{{cite journal |doi= 10.1126/science.7871434|year=1995 |last1=Cross |first1= Shawn M. | last2=Sanchez |first2=Carissa A| last3=Morgan |first3= Catherine A. |last4=Schimke |first4= Melana K. |last5=Reid|first5= Brian J.| journal=Science|volume=3 |issue= 5202 |pages= 1353–1356|title= A p53-dependant mouse spindle checkpoint|pmid=7871434 |bibcode=1995Sci...267.1353C |s2cid=38128370 }}</ref>  Another key aspect of cancer is inhibition of cell death or [[apoptosis]]. [[Survivin]], a member of the inhibitor of apoptosis (IAP) family, is localized in pools at microtubules of the mitotic spindle near the centrosomes and at the kinetochores of metaphase chromosomes. Not only does survivin inhibit apoptosis to promote tumorigenesis, but it has been implicated (through experimental knockout mice) as an important regulator of chromosome segregation, and late stage mitosis similar to its role in more primitive organisms.<ref name="Altieri2001">{{cite journal | vauthors = Altieri DC | title = The molecular basis and potential role of survivin in cancer diagnosis and therapy | journal = Trends in Molecular Medicine | volume = 7 | issue = 12 | pages = 542–7 | date = December 2001 | pmid = 11733216 | doi = 10.1016/S1471-4914(01)02243-2 }}</ref>

Other aspects of the spindle assembly checkpoint such as kinetochore attachment, microtubule function, and sister chromatid cohesion are likely to be defective as well to cause aneuploidy. Cancer cells have been observed to divide in multiple directions by evading the spindle assembly checkpoint resulting in multipolar mitoses.<ref name="Gisselsson2008">{{cite journal | vauthors = Gisselsson D, Håkanson U, Stoller P, Marti D, Jin Y, Rosengren AH, Stewénius Y, Kahl F, Panagopoulos I | title = When the genome plays dice: circumvention of the spindle assembly checkpoint and near-random chromosome segregation in multipolar cancer cell mitoses | journal = PLOS ONE | volume = 3 | issue = 4 | pages = e1871 | date = April 2008 | pmid = 18392149 | pmc = 2289843 | doi = 10.1371/journal.pone.0001871 | bibcode = 2008PLoSO...3.1871G | doi-access = free }} {{open access}}</ref> The multipolar metaphase-anaphase transition occurs through an incomplete separase cycle that results in frequent nondisjunction events which amplify aneuploidy in cancer cells.