An updated view on the centrosome as a cell cycle regulator

Abstract

The centrosome is a multifunctional organelle that is known primarily for its microtubule organising function. Centrosomal defects caused by changes in centrosomal structure or number have been associated with human diseases ranging from congenital defects to cancer. We are only beginning to appreciate how the non-microtubule organising roles of the centrosome are related to these clinical conditions. In this review, we will discuss the historical evidence that led to the proposal that the centrosome participates in cell cycle regulation. We then summarize the body of work that describes the involvement of the mammalian centrosome in triggering cell cycle progression and checkpoint signalling. Then we will highlight work from the fission yeast model organism, revealing the molecular details that explain how the spindle pole body (SPB, the yeast functional equivalent of the centrosome), participates in these cell cycle transitions. Importantly, we will discuss some of the emerging questions from recent discoveries related to the role of the centrosome as a cell cycle regulator.

Keywords: Cancer; Cell cycle; Centrosome; SPB.

Fig. 1

Regulation of cell cycle progression from the centrosome. The centrosome plays an important role as a signalling hub during the cell cycle. It facilitates the G1-S transition (top left) and the G2-M transition (bottom left) by recruiting key cell cycle players to the centrosome. The centrosome is also linked to the checkpoint signalling by anchoring the DNA damage checkpoint proteins (right) and the PIDDosome (centre). In the presence of cellular stress such as centrosome amplification and DNA damage, the centrosome promotes the checkpoint responses, which directly or indirectly inhibit the Cdk-Cyclin complexes and arrest the cell cycle

Fig. 2

Localised activation of Plk1^Plo1 at the yeast SPB reinforces the pro-mitotic signalling to drive cells into mitosis. The recruitment of PP1^Dis2 to Cut12 negatively regulates the recruitment of Plk1^Plo1 at the yeast spindle pole body (SPB). In G2, 30 min before mitosis, Nek2^Fin1 and Cdk1^Cdc2 activation at the centrosome expels PP1^Dis2 from the SPB by phosphorylating the residues T75 T78 on Cut12. The disassociation of PP1^Dis2 from the SPB allows the recruitment and activation of Plk1^Plo1 at the SPB. The activation of Plk1^Plo1 promote the inhibition of Wee1 and facilitates Cdc25 activation, reinforcing the commitment into mitosis by favouring the activation of Cdk1^Cdc2

Fig. 3

Crosstalk between two SPB scaffolds demonstrates the integration of signalling to promote cell cycle transitions. a A cartoon depicting the integration of signalling at the yeast SPB. It was previously thought that signalling scaffolds such as Cut12 and Sid4 work independently to promote cell cycle events and are functionally and temporally separated (top). Recent work shows that crosstalk between two functionally distinct signalling scaffolds occurs, working together to promote mitotic entry (bottom). b Model of the centrosomal signalling on Sid4 triggering mitosis. In mid G2, Nek2^Fin1 recruits CSNK1D^Hhp2 by phosphorylating Sid4 at residue T584. Recruitment of CSNK1D^Hhp2 results in the phosphorylation of residue T275 and S278. This recruits Chk2^Cds1 that phosphorylates Cdc14^Flp1, expelling the phosphatase from the SPB. The absence of Cdc14^Flp1 allows Cdk1-Cyclin B to activate the SPB triggering mitotic entry (CC: coiled-coil domain; SID: Sid domain, conserved N-terminal domain of Sid4)