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

which sister-chromatids are not properly bi-oriented. Several erroneous attachments can occur, such
as monotelic or syntelic, in which only one or both sister kinetochores respectively are attached to
one spindle pole, or merotelic attachments resulting in one sister kinetochore being attached to both
spindle poles (Fig.3). To prevent anaphase onset in the presence of these aberrant attachments, an
error-correction machinery has evolved in which the mitotic kinase Aurora B plays an essential role53- 56 . Aurora B is part of the chromosomal passenger complex (CPC), which localizes to the centromeric
region of the kinetochore during (pro) metaphase (reviewed in 57 ) and phosphorylates many (outer)
kinetochore substrates, which eventually results in destabilization of erroneous kinetochore-MT
interactions 53-56 .
In some cases, substrate phosphorylation by Aurora B affects the static interactions between
microtubule-binding proteins and the MT interface, such as phosphorylation of members of the
KMN network 58-60 or CENP-E61 . Phosphorylation of the microtubule depolymerase MCAK, however, is
thought to directly affect its depolymerizing activity62-65 .
The model for Aurora B-dependent error-correction is that establishment of tension in between
two sister kinetochores upon MT-binding will spatially restrict Aurora B phosphorylation of
outer kinetochore substrates66 . Bi-orientation and tension across sisters will promote the
dephosphorylation of Aurora B substrates and will eventually result in stable kinetochore-MT
attachments60,61,67 . Erroneous attachments, such as merotelic or syntelic attachments, lead to
incomplete establishment of tension in between the two sister-kinetochores, which gives Aurora B
the opportunity to phosphorylate its targets and destabilize the faulty kinetochore-MT interactions
64,66 .
Amphitelic
(bioriented)
Monotelic Syntelic
Merotelic
Figure 3. Schematic representation of the various types of kinetochore microtubule interactions
Normal (amphitelic) bi-orientation is achieved when each sister-kinetochore is attached to microtubules coming from one spindle
pole. Erroneous interactions occur when one sister kinetochore is unattached (monotely), attached to two poles (merotely), or
when both sister kinetochores are attached to one pole (syntely).
2.3 Monitoring attachment status: the Mitotic Checkpoint
Sophisticated mechanisms have evolved to organize kinetochore-MT attachments in such a way
that proper bi-orientation of sister chromatid pairs is being achieved during every mitotic cycle. To
allow time to fulfill these dynamic processes, the mitotic checkpoint or spindle assembly checkpoint
(SAC) has evolved (Fig.4). From the initial observations that anaphase was only initiated after all
kinetochores were attached to MTs 68,69 and that laser-ablating the last unattached kinetochore
resulted in anaphase onset 70 , it was postulated that the mitotic checkpoint consists of an inhibitory
signal that originates from unattached kinetochores and delays anaphase progression 70 . A couple of
13
General Introduction 1