Biology Reference
In-Depth Information
kinase is recruited to this site, which leads to recruitment of a Sas-5/Sas-6
complex that forms a hollow cylinder that recruits Sas-4, which determines
centriole length and leads to assembly of centriolar microtubules. Many of these
proteins have mammalian orthologs that regulate centriole assembly: Cdk2
triggers centrosome duplication, and both cyclin A and cyclin E direct Cdk2 to
relevant centriolar substrates including NPM/B23 (Okuda et al.
2000
), CP110
(Chen et al.
2002
), and Mps1 (Kasbek et al.
2007
) [reviewed in (Hinchcliffe and
Sluder
2002
)]. Cep192, the human ortholog of SPD-2 regulates centriole
assembly and binds to Plk4 (Franck et al.
2010
), the distant relative and pre-
sumptive functional counterpart to ZYG-1. Plk4 then leads to recruitment of
hSas6, the human ortholog of Sas-6 (Strnad et al.
2007
; Kleylein-Sohn et al.
2007
), and CPAP/CENP-J, the human ortholog of Sas-4, (Tang et al.
2009
;
Schmidt et al.
2009
; Kohlmaier et al.
2009
), regulates centriole length. How-
ever, there are important differences between worms and humans. Notably,
hSas6 forms the hub of a cartwheel structure that serves as a template around
which a centriole is assembled, rather than the hollow tube seen in C. elegans,
and vertebrate centrioles contain triplet microtubules rather than singlets.
Moreover, in humans many additional proteins not found in worms regulate
centriole assembly. For example, recruitment of Plk4 to the site of centriole
assembly additionally requires the human ortholog of D. melanogaster asterless,
Cep152 (Cizmecioglu et al.
2010
; Hatch et al.
2010
; Dzhindzhev et al.
2010
),
and centriole assembly and elongation involves additional factors such as
Cep135 (Kleylein-Sohn et al.
2007
; Kim et al.
2008
), c-tubulin, and CP110
(Kleylein-Sohn et al.
2007
; Spektor et al.
2007
), as well as d- and e- tubulins
(Chang and Stearns
2000
; Chang and Giddings
2003
), Mps1 (Kasbek et al.
2007
; Yang et al.
2010
; Fisk et al.
2003
), Centrin 2 (Yang et al.
2010
; Salisbury
et al.
2002
), hPoc5 (Azimzadeh et al.
2009
), and Cep76 (Tsang et al.
2009
),
among others.
While a combined proteomics and comparative genomics study found just 18
core centriole proteins in the unicellular green algae C. reinhardtii (Keller et al.
2005
), proteomics analysis estimated at least 150 proteins present at the human
centrosome (Andersen et al.
2003
). One interesting feature of the centrosomal
proteome is that many components of the proteasome were found at centro-
somes. Indeed, several centriole assembly factors whose overexpression leads to
the production of excess centrosomes have been shown to be controlled by
proteasome-dependent degradation, including Mps1 (Kasbek et al.
2007
,
2010
;
Fisk and Winey
2001
), Plk4 (Guderian et al.
2010
; Cunha-Ferreira et al.
2009
),
and Sas6 (Strnad et al.
2007
), and failure to properly control degradation of
these proteins causes the production of excess centrioles within a single cell
cycle, also known as centrosome re-duplication. Moreover, many E3 ubiquitin
ligases have been implicated in the control of centrosome function, as have
ubiquitin-independent proteasome degradation and non-proteasomal proteolysis.
In this chapter we will review the evidence linking these pathways to centro-
some function.
