Chromosome segregation errors: a double-edged sword - TI Pharma

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tumor types than mutation of mitotic checkpoint components. However, it still remains largely
unknown how overexpression of mitotic checkpoint genes, such as MAD2, could result in chromosome
missegregations and this will need further investigation.
4.3.2 Cohesion loss
Duplicated sister chromatids are held together until anaphase by the centromeric cohesin complex.
Maintenance of cohesion between the two sister centromeres is essential for chromosome biorientation
and hence for proper chromosome segregation 334-336 . Loss of cohesion before anaphase
results in premature sister chromatid separation, which eventually results in chromosome segregation
errors and aneuploidy (Fig.6B). Various genes encoding for proteins involved in cohesion establishment
or maintenance have been found to be mutated in aneuploid tumors 335,337 . In addition, a recent report
observed frequent deletion of an X-chromosome-linked region in genetically unstable tumor samples 338 .
This locus encodes for SA2, which is a subunit of the cohesin complex. Interestingly, targeted inactivation
of this locus, termed STAG2, resulted in chromosomal instability in otherwise chromosome-stable
near-diploid cells. Moreover, reconstitution of STAG2 in CIN tumor cells, which harbor a deletion of the
endogenous locus, reverted the CIN phenotype and enhanced chromosomal stability in these lines 338 .
Defective sister chromatid cohesion as a result of somatic mutations may represent a major
cause of CIN in human cancers. In line with this, overexpression of Separase, the protease that
cleaves cohesin upon mitotic exit, has been observed in breast cancer samples 339 and transient
overexpression of Separase can also result in anaphase bridges and aneuploidy in human cells 339 .
Besides its role in sister chromatid cohesion, cohesin has also been implicated in DNA replication,
DNA damage and protection of telomeres 340 . Therefore, various other mechanisms might underlie
the aneuploidy observed in cells that have mutations in one of the cohesin subunits 341 and further
research is needed to investigate in cohesion defects in the establishment of CIN.
4.3.3 Merotelic attachments
Although CIN cell lines do not necessarily possess a weakened mitotic checkpoint, many CIN cell lines
do have an increased occurrence of lagging chromosomes due to unresolved merotelic attachments
to the mitotic spindle 289,342 (Fig.6C). Because merotelic attachments link one kinetochore to two
spindle poles, the sister chromatid has an increased chance of ending up in between the two packs
of DNA during anaphase 343,344 . Most merotelic attachments are resolved by the error-correction
machinery before anaphase 248,345,346 . However, tension can be established on a kinetochore despite
merotelic attachments, causing Aurora B not to correct the erroneous attachments 344 . Moreover,
since merotelic attachments do not prohibit kinetochores to obtain full microtubule occupancy,
they do not necessarily activate the mitotic checkpoint 344 . Such merotelic attachments could
therefore persist into anaphase and lead to chromosome missegregations and aneuploidy 289,344 .
Multiple cellular, genetic and molecular causes of merotelic attachments have been hypothesized, of
which the most significant ones are outlined below.
Aberrant spindle morphology
One way in which merotelic attachments could arise is through abnormal spindle assembly. Initial clues
on this mechanism came from the observation that multipolar spindle assembly in kangaroo cells often
led to kinetochore-binding to two spindle poles 347 . These merotelic attachments were not sensed by
the mitotic checkpoint and often resulted in lagging chromosomes in anaphase 348 . These data indicate
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