Figure 2. Key aspects of the centrosome duplication cycle.

(A) Mitotic events licensing a new round of centriole duplication. Schematic describing four major events that occur during the progression from late G2 through M and into early G1. All four events, distancing, removal of the cartwheel, centriole disengagement and centriole-to-centrosome conversion, are considered necessary for the licensing of centrioles for a new round of duplication. Although the four events are conceptually distinct, they are expected to be integrated at a molecular and structural level.

(B) The birth of a new centriole. The master regulator PLK4 is initially recruited to a ring of CEP152 and CEP192 at the proximal end of the parent centriole. According to one model (I), a symmetry breaking event triggers accumulation of active PLK4 at one single site (dot) on the ring. The mechanism underlying symmetry breaking remains to be understood, but presumably involves self-enforcing feedback loops centered on PLK4, STIL, proteases and yet unidentified phosphatases. An alternative model (II) attributes an important role to the lumen of the parent centriole in assisting SAS-6 self-assembly into a cartwheel structure. PLK4 and STIL subsequently cooperate to remove the pre-formed cartwheel scaffold from the mould and position it laterally on the parent centriole.

(C) Coming of age: centriole and centrosome maturation. A G2 cell typically comprises 2 pairs of centrioles. The two parent centrioles are initially connected by a loose tether and form a single microtubule-organizing center. This tether is removed by a shift in the balance of activities of the NEK2 kinase and an opposing type 1 phosphatase (PP1α) acting on C-Nap1/CEP250 and other substrates^118,119,205. Subsequently, the two centrosomes are separated by the microtubule-dependent motor EG5 (and the partially redundant motor KIF15)²⁰⁶, with EG5 being recruited to centrosomes in response to CDK1 phosphorylation²⁰⁷. Entry into mitosis requires expansion of PCM, termed centrosome maturation, in preparation for mitotic spindle formation. This step is triggered by PLK1 and Aurora A and results in the sequential recruitment of CEP152/Asl, CEP215/Cnn and CEP192/DSpd-2. Finally, only one parent centriole is fully mature (i.e. carries appendages) in a G2 cell, but during G2 and/or M phase the second parent centriole matures and acquires appendages in an event triggered by PLK1¹²¹. Centrioles are depicted in different shades of grey and PCM in different shades of brown, to indicate different states of maturity. Cartwheels are shown in red; loose tethers connecting parent centrioles as dashed green lines; tight linkers connecting procentrioles to their parents in dark blue; subdistal and distal appendages in light and dark blue respectively.