Centrosomes, DNA Damage and Aneuploidy - The Centrosome - page 220

et al. 1995 ; Meraldi et al. 2002 ). Amplification of the centrosome occurs in cells
that carry mutations in DNA repair or checkpoint genes (Bertrand et al. 2003 ;
Dodson et al. 2004 ; Fukasawa et al. 1996 ; Griffin et al. 2000 ; Kraakman-van der
Zwet et al. 2002 ; Mantel et al. 1999 ; Tutt et al. 2002 ; Yamaguchi-Iwai et al. 1999 ),
express mutant forms of telomerase (Guiducci et al. 2001 ) or express viral
oncogenes (Duensing et al. 2006 ; Duensing et al. 2000 ; Duensing and Munger
2003 ; Watanabe et al. 2000 ). Although these examples cover a broad range of
genotoxic insults, it is clear that centrosome amplification is a potential conse-
quence of DNA damage.
13.6 Mechanisms that Permit Centrosome Amplification
Multiple centrosomes can be observed in cells that suffer failure in cytokinesis due
to altered expression of cell cycle and checkpoint regulators such as p53, BRCA2
and Aurora A (Daniels et al. 2004 ; Meraldi et al. 2002 ). In general, DNA-dam-
aging treatments do not lead to tetraploidisation, so cytokinesis failure is not
sufficient to explain how centrosome amplification occurs after genotoxic stress.
Additional models are required, which we consider below.
Given the importance of ensuring the right number of centrosomes, normal
centrosome duplication occurs in a manner that is strictly co-ordinated with the
cell cycle (Delattre and Gonczy 2004 ; Hinchcliffe and Sluder 2001 ; Nigg 2007 ).
This coordination is ensured by at least two controls:
i. A requirement for cyclin-dependent kinase activity in centrosome duplication.
A specific link between the chromosome and centrosome cycles is CDK2,
which requires heterodimerisation with cyclin A or cyclin E for activity and
which is necessary for the centrosome duplication that occurs during extended
S-phase arrest in mammalian cells (Hinchcliffe et al. 1999 ; Lacey et al. 1999 ;
Matsumoto et al. 1999 ; Meraldi et al. 1999 ), but not in chicken DT40 cells
(Bourke et al. 2010 ). Cdk2 is also necessary for the centriole overduplication
that is induced by expression of the human papillomavirus (HPV) type 16 E7
oncoprotein or by proteasome inhibition (Duensing et al. 2007 ; Duensing et al.
2006 ). However, Cdk2 is not required in mouse or chicken cells for normal
centrosome duplication and it is likely that other kinases can compensate for its
absence in the cell cycle (Adon et al. 2010 ; Duensing et al. 2006 ; Hochegger
et al. 2007 ).
ii. A 'licensing' of centrosome duplication through centriole disengagement,
which is mediated by Polo-like kinase 1 and separase, a protease that is
activated through anaphase promoting complex/cyclosome activity at the
metaphase-anaphase transition (Tsou and Stearns 2006 ; Tsou et al. 2009 ).
This licencing requirement normally limits when cells can duplicate their
centrosomes, even within a cytoplasm that contains the requisite Cdk activity
(Wong and Stearns 2003 ).