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

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1.4 NoCut: preventing the induction of tetraploidy or DNA damage?
The NoCut pathway, initially identified in budding yeast, is thought to protect the chromatin from
abscission-induced DNA damage in yeast 197 . The purpose of NoCut pathway activation seems to differ
between species, since inhibition of the homologues pathway in human cells resulted in tetraploidy
rather than chromatin breakage by the abscission machinery 196 . In addition, we observed that DNA
damage on lagging chromosomes occurs already in telophase, before the induction of abscission
(Chapter 2). RPE cells do elicit an active NoCut response, since we observed localization of several
active NoCut components to the site of abscission in the presence of chromatin bridges (data not
shown). These data together indicate that the NoCut pathway in human cells cannot prevent DNA
damage from occurring during cytokinesis, which suggests that the NoCut pathway in human cells has
indeed primarily been preserved to prevent tetraploidy rather than to inhibit DNA damage induction
on chromatin bridges, as in budding yeast 197 . Interestingly, however, a recent report in which the
abscission mediator ESCRT III was identified as mediator of the NoCut pathway in human cells,
showed that depletion of the ESCRT III subunit CHMP4C resulted in premature chromatin resolution
in anaphase and increased DNA damage 628 , but did not result in overt tetraploidy. This contradiction
raises the question whether the NoCut or abscission checkpoint has been preserved in humans to
protect genome stability by inhibiting DNA damage on lagging chromatin, by inhibiting the formation
of tetraploid cells or both 196,628 .
2. How do chromosome segregation errors contribute to tumorigenesis?
Boveri was the first to postulate that chromosomal aberrations could be a causal factor in the occurrence
of cancer 232 after von Hansemann had observed the presence of chromosomal abnormalities and
mitotic errors in cancer cells 233 . At present, the impact of structural changes on cancer progression
is quite well understood 240 , while the effects of numerical changes on tumorigenesis remain highly
debated 267,398 . Although some of the CIN mouse models develop spontaneous tumors late in life
(Chapter 1), the question remains whether CIN and aneuploidy are causes or consequences of cancer
development.
2.1 Chromosomal instability in tumorigenesis
Chromosomal instability (CIN) has been observed in early neoplastic lesions 629 and is thought to be
able to cause transformation 397,630,631 . In addition, aneuploidy, one of the common consequences of
CIN, can drive evolution by introducing phenotypic variation in several budding yeast strains 632,633 . In
line with a role for CIN in tumorigenesis, CIN has been associated with poor prognosis and resistance
to chemotherapeutics in human patients 271-280 . Indeed, overexpression of the mitotic checkpoint
protein MAD2, which results in CIN 331,332 , has also been shown to be able to drive tumor relapse
in mice following Kras inhibition, indicating that CIN could overcome oncogene-addiction and
affect chemotherapeutic responses 409 . However, not all CIN mouse models develop spontaneous
or carcinogen-driven tumors despite clear aneuploidy induction 295,297,300,412,414,415 . Moreover, CIN has
also been associated with tumor suppression 286,401,404,405 , indicating that the link between CIN and
tumorigenesis remains unclear and that multiple factors likely affect the tumor promoting capacity of
CIN and aneuploidy.
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