Biology Reference
In-Depth Information
2005
). Plk1 plays an important role in the maturation of centrosomes. Inhibition of
this kinase results in the formation of significantly smaller centrosomes with a
decreased gamma-tubulin localization (Lane and Nigg
1996
). Plk2 and 4 localize
to the centrosome and their depletion suppresses the initiation of centrosome
duplication (Habedanck et al.
2005
; Warnke et al.
2004
). Similarly, Plk3 is found
at the centrosome during interphase, it then co-migrates with duplicated centro-
somes at all stages of the cell cycle (Wang et al.
2002
). Aurora kinases (A, B, and
C) are serine/threonine kinases whose expression is known to be elevated in many
human cancers (Li and Li
2006
). Their activity levels are highest during the G2-M
phase of the cell cycle.
Aurora kinase A (AURKA) localizes to the centrosomes and is essential for
mitotic progression. AURKA interacts with several centrosomal and centrosome
regulating proteins and its overexpression results in supernumerary centrosomes
(Meraldi et al.
2002
) whereas its inhibition causes the formation of monopolar
spindles (Glover et al.
1995
). Thus, AURKA plays a crucial role in the regulation of
centrosome separation and duplication. AURKC also localizes to the centrosome and
its overexpression results in polyploidy cells with more than two centrosomes
(Dutertre et al.
2005
). Nek2, a member of the Nek (NIMA)-related kinases, has also
been implicated in the regulation of centrosomes. Nek2 phosphorylates centrosomal
Nek2-associated protein 1 (C-Nap1) triggering the dissociation of C-Nap1 from the
centrosomes to mediate the centrosomal separation (Fry et al.
1998a
; Mayor et al.
2002
). Overexpression of Nek2 results in premature splitting of the centrosomes
(Fry et al.
1998b
).
14.2.4 DNA Damage Repair Proteins and the Regulation
of the Centrosome
Recent studies have indicated the involvement of several DNA damage and repair
proteins in the maintenance of the centrosome (Fukasawa et al.
1996
; Griffin et al.
2000
; Kraakman-van der Zwet et al.
2002
; Shimada et al.
2009
; Yamaguchi-Iwai
et al.
1999
). In addition, several studies have stressed on the importance of
homologous recombination (HR) repair proteins in the regulation of the centro-
some (Shimada and Komatsu
2009
; Shimada et al.
2009
). HR is a major pathway
through which DNA double-stranded breaks are repaired. Several repair proteins
take part in this pathway and these include: ATM/ATR kinases, NBS1-MRE11-
RAD50 complex, BRCA1, and BRCA2. ATM is a serine/threonine kinase that is
activated by autophosphorylation as an initial step of the DNA damage response.
ATM localizes to the centrosome and regulates centrosome number through the
cell cycle checkpoint (Oricchio et al.
2006
; Shimada and Komatsu
2009
). ATR
also localizes to the centrosome and depletion of this protein leads to centrosome
amplification (Collis et al.
2008
).
