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

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The CCAN network is thought to create a stable environment for mitotic assembly of the outer
kinetochore 20,24 , which consists of proteins that are important for the interaction with the
plus-ends of spindle microtubules (MTs) such as the MT-binding KMN network, consisting of
Knl1 25 , the Mis12 complex 26 and the Ndc80 complex 27-30 . The KMN network is an evolutionary
conserved network 31 of which only Knl-1 and the Ndc80 complex have direct MT-binding
capacity, but the complete network acts synergistic in acquiring full MT binding capacity 31 .
Another outer kinetochore component that directly controls the kinetochore microtubule
interaction is the recently identified SKA complex in human cells 32-37 , of which it is hypothesized
that it might function as the ring-shaped Dam1 complex found at budding yeast kinetochores 38-40 .
The kinesin CENP-E is another important MT-binding protein identified at the outer kinetochore and
is required to move polar chromosomes to the spindle equator and promote proper kinetochore-
centromeric DNA
CENP-A nucleosomes
Figure 2. Build-up of centromeres and kinetochores
Centromeres are defined by the presence of CENP-A nucleosomes and form the kinetochore assembly sites on chromosomes.
Kinetochores consist of an inner- and outer compartment, of which the inner kinetochore is made up of CCAN proteins and the
outer kinetochore recruits a variety of microtubule binding proteins to establish stable microtubule interactions.
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CCAN
outer kinetochore
microtubules
Mis12
Ndc80
Knl-1
CENP-E
MT attachments 41,42 . Besides these MT-binding proteins that are thought to be directly responsible
to create stable kinetochore-microtubule interactions, over 80 other outer kinetochore proteins have
been identified over the years (reviewed in 19,43 ). These include other microtubule-binding proteins,
such as CLIP-170 44,45 , MCAK 46 , Dynein 47,48 and CLASPs 49 , but also non-microtubule-binding proteins
such as Plk1 50 , CENP-F 51 and all mitotic checkpoint proteins important in monitoring the kinetochore-
MT attachment status (see below section 2.3). All these kinetochore proteins together create an
environment that allows efficient chromosome alignment at the metaphase plate and eventually
proper chromosome segregation.
2.2 Error-correction
To ensure proper chromosome segregation in anaphase, sister-kinetochores of each chromatid pair
should be facing opposite spindle poles, also referred to as bi-orientation. The above described MTnucleating
and capturing events often result in ‘aberrant’ attachments 52 , which are attachments in
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