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In several instances given above (Bettencourt-Dias et al. 2005 ; Habedanck et al.
2005 ; Kleylein-Sohn et al. 2007 ; Peel et al. 2007 ; Strnad et al. 2007 ), overex-
pression of the key upstream regulators of centriole duplication causes the for-
mation of multiple daughter centrioles. However, in a preliminary study on a
subset of centrosomal candidates, we found no evidence for significant upregu-
lation of centrosome protein-coding genes after irradiation of non-transformed
human cells (Saladino 2010 ), suggesting that increasing the levels of the structural
components of new centrioles is not how IR drives centrosome amplification.
Another question that arises is how additional centrioles assemble after irradiation,
once the conditions that allow their overduplication have been met. Time-lapse
microscopy of CHO cells during extended S-phase arrest has indicated that mul-
tiple centrosomes can assemble around the pre-existing mother (Guarguaglini et al.
2005 ; Kuriyama et al. 2007 ), or from nuclear aggregates of centrin (Prosser et al.
2009 ). Multiple daughters are also induced by peptide vinyl sulfone proteasome
inhibitor Z-L(3)VS treatment (Duensing et al. 2007 ) or by the HPV16 E7 onco-
protein (Duensing et al. 2006 ). However, apart from centriole splitting and
fragmentation, which may reflect initial steps in centrosome reduplication, it
appears that IR induces the duplication of the entire centrosome in the form of
paired mother-daughter centrioles (Bourke et al. 2007 ; Dodson et al. 2007 ).
13.8 IR Impact on the Cell Cycle and on Cells
IR and other forms of DNA damage kill cells through caspase-dependent apoptosis or
mitotic catastrophe (Blagosklonny 2007 ; Jonathan et al. 1999 ; Okada and Mak 2004 ;
Roninson et al. 2001 ). Mitotic catastrophe is a consequence of a mitotic delay in which
cells with incompletely replicated genomes or unrepaired DNA damage enter mitosis
and undergo apoptosis during M phase (reviewed by Vakifahmetoglu et al. 2008 ).
While the G2 checkpoint normally averts mitotic entry under such circumstances,
problems with this checkpoint can allow cells to initiate premature mitosis, suffer
mitotic delay through activation of the SAC and ultimately, die (Johnson et al. 1999 ;
Mikhailov et al. 2002 ; Nitta et al. 2004 ;Shinetal. 2003 ;Vogeletal. 2005 ). Centrosome
amplification, a response to DNA damage that occurs during a checkpoint-mediated
delay, will also cause a mitotic delay and compromise cell viability during such a delay
(Ganem et al. 2009 ; Inanc et al. 2010 ;Loffleretal. 2006 ). In support of the notion that
centrosome amplification contributes to the death of cells with DNA damage, live-cell
imaging analysis of human tumour cells demonstrated that the vast majority of
irradiated cells with multiple centrosomes fail in mitosis, but also that[60 % of cells
undergoing mitotic catastrophe have multiple centrosomes (Dodson et al. 2007 ).
As noted in a recent review of how aneuploidy arises, it is not yet clear whether
centrosome amplification is a cause or a consequence of genome instability, or both
(Chandhok and Pellman 2009 ). It is clear that a deficiency in the DNA damage
response is likely to lead toward cancer. Recent data have demonstrated the activation
of the DNA damage response in pre-cancerous lesions in a range of human tissues
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