Regulation of the Centrosome Cycle by Protein Degradation - The Centrosome - page 153

Rbx1, and a linker subunit, Skp1, that, as in the APC/C, catalyze the transfer of
ubiquitin from the E2 enzyme to the substrate.
9.2 The Centrosome Cycle
Being a single copy organelle, the centrosome is duplicated just once during each
cell cycle. Hence, cells enter mitosis with two centrosomes that give rise to two
spindle poles. This process ensures both spindle bipolarity and inheritance of a
single centrosome by each daughter cell. The centrosome cycle must therefore
proceed in a timely fashion that is carefully coordinated with the cell cycle. Failure
to coordinate these events could lead to the generation of supernumerary centro-
somes and genetic instability (Nigg 2007 ; Tsou and Stearns 2006 ).
The centrosome cycle can be viewed as four discrete steps: centriole duplication,
centrosome maturation, centrosome disjunction, and centriole disengagement.
Centriole duplication commences in S-phase with the appearance of procentrioles
lying perpendicular and in very close proximity to the proximal ends of the existing
centrioles. This association establishes the tight orthogonal arrangement of the
parental and progeny centrioles that is maintained through to late mitosis. The two
procentrioles elongate in a proximal to distal direction, reaching full length in G2. In
late G2, centrosome maturation (or enlargement) occurs through recruitment of
additional pericentriolar material (PCM) in preparation for the increased microtu-
bule nucleating activity required in mitosis. However, the duplicated centrosome,
now containing four centrioles, still continues to act as a single microtubule orga-
nizing center due to the presence of a loose tether that links the proximal ends of the
parental centrioles throughout interphase. As cells progress from G2 into mitosis,
centrosome disjunction occurs and the tether is severed. The physical separation of
the two centrosomes in space is driven by motor proteins and ultimately gives rise to
the two poles of the mitotic spindle. The centrosome cycle is completed with cen-
triole disengagement in late mitosis. Each centriole pair, residing at the spindle poles,
loses its tight orthogonal attachment, thereby licensing centriole duplication in the
next cell cycle. As cells enter G1, the pair of now disengaged centrioles become
tethered once again through their proximal ends regenerating the single microtubule
organizing center typical of an interphase cell.
Together, these events are subjected to strict spatial and numerical control to
ensure that the centrosome cycle occurs once and only once per cell cycle (Nigg
and Stearns 2011 ). In line with the classical cell cycle, the centrosome cycle is also
subject to control by both reversible phosphorylation and irreversible protein
degradation (Fig. 9.1 ). It has been known for more than a decade now that com-
ponents of both the APC/C and SCF ubiquitin ligases localize to the centrosome
putting them in position to directly regulate events of the centrosome cycle (Freed
et al. 1999 ; Raff et al. 2002 ). Indeed, mechanistic details are now beginning to
emerge about how the process of protein degradation controls different events of
the centrosome cycle, as described below.