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observations supported the theory that amplified centrosomes represent a cause of
aneuploidy, they did not establish how the two phenomena are related or whether
centrosome amplification was a cause or a consequence of cancer progression
(reviewed by D'Assoro et al. 2002b ; Nigg 2002 ).
13.3 Mechanisms of Aneuploidy that Involve
Centrosome Amplification
Conceptually, the simplest mechanism of aneuploidy to arise from centrosome
aberrations is that multipolar mitoses occur through the formation of multiple
spindle poles and cause aneuploidy through unequal distribution of chromo-
somes between daughter cells (Fukasawa 2005 ). However, recent time-lapse
video microscopy studies demonstrated that cultured human cells containing
amplified centrosomes efficiently cluster their extra centrosomes and divide in a
bipolar fashion. Only a small fraction of cells with extra centrosomes under-
went multipolar division and the progeny originating from such divisions was
mostly non-viable (Ganem et al. 2009 ), consistent with the view that massive
aneuploidy induced by multipolar cell division is lethal. Similarly, analysis of
Drosophila lines in which around 60 % of the cells possessed supernumerary
centrosomes revealed a delay in mitosis due to the formation of a transient
multipolar intermediate, but the cells ultimately divided in a bipolar fashion
(Basto et al. 2008 ).
Centrosome clustering appears to be the major strategy that human cells employ
to minimise the impact of multiple centrosomes (Quintyne et al. 2005 ), although
there exist several other approaches, such as inactivation or sequestration of extra
centrosomes (Gergely and Basto 2008 ; Godinho et al. 2009 ). However, even
though centrosome clustering prevents lethality caused by multipolar division,
centrosome amplification, nevertheless, leads to chromosome missegregation and
instability (Ganem et al. 2009 ; Silkworth et al. 2009 ). A recent study suggested a
novel potential mechanism for how supernumerary centrosomes cause chromo-
some aberrations and aneuploidy. Pellman and colleagues showed that cells with
amplified centrosomes go through a transient multipolar state during spindle for-
mation, before clustering their centrosomes (Ganem et al. 2009 ). This intermediate
state predisposes cells to develop aberrant merotelic attachments with high fre-
quency. Unresolved merotelic attachments impair chromosome segregation by
causing lagging chromosomes during anaphase (Cimini et al. 2001 ; Gregan et al.
2011 ), so that this model provides an explanation for how multiple centrosomes
can lead to chromosome abnormalities, without causing multipolar divisions.
Therefore, how cells acquire multiple centrosomes is an important question in
understanding how genome stability is normally maintained.
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