Degradation of Cep68 and PCNT cleavage mediate Cep215 removal from the PCM to allow centriole separation, disengagement and licensing

Abstract

Summary An intercentrosomal linker keeps the cell’s two centrosomes joined together until it is dissolved at the onset of mitosis. A second connection keeps daughter centrioles engaged to their mothers until they lose their orthogonal arrangement at the end of mitosis. Centriole disengagement is required to license centrioles for duplication. We show that the intercentrosomal linker protein Cep68 is degraded in prometaphase through the SCFβTrCP (Skp1-Cul1-F-box protein) ubiquitin ligase complex. Cep68 degradation is initiated by PLK1 phosphorylation of Cep68 on Ser332, allowing recognition by βTrCP. We also found that Cep68 forms a complex with Cep215/Cdk5Rap2 and PCNT/Pericentrin, two PCM (pericentriolar material) proteins involved in centriole engagement. Cep68 requires two different pools of Cep215. We propose that Cep68 degradation allows Cep215 removal from the peripheral PCM preventing centriole separation following disengagement, whereas PCNT cleavage mediates Cep215 removal from the core of the PCM to inhibit centriole disengagement and duplication.

A centrosomal scaffold shows some self-control

“…This result raises the possibility that AKAP350A may regulate centriole linkage (Fig. 1B, Q1), perhaps complementing the recentlyidentified role for pericentrin (6).…”

The C-terminal region of A-kinase anchor protein 350 (AKAP350A) enables formation of microtubule-nucleation centers and interacts with pericentriolar proteins

“…Cep68 together with Cdk5RAP5 were shown previously to play roles in centrosome cohesion and engagement in interphase (45,47,49). Plk1 phosphorylation of Cep68 at Ser-322 initiates the degradation of Cep68 during prometaphase, allowing Cdk5RAP2 removal and centriole disengagement (47). Cep68 is also phosphorylated by Nek2A both in vitro and in vivo (13,28,50), and this phosphorylation also promotes Cep68 degradation in mitosis.…”

“…Cep68 together with Cdk5RAP5 were shown previously to play roles in centrosome cohesion and engagement in interphase (45,47,49). Plk1 phosphorylation of Cep68 at Ser-322 initiates the degradation of Cep68 during prometaphase, allowing Cdk5RAP2 removal and centriole disengagement (47).…”

“…Rootletin forms centriole-associated fibers and is implicated in centrosome cohesion (46). Cep68 is degraded in prometaphase, allowing centrosome separation, and Cep68 degradation is initiated by its phosphorylation on serine 332 by Plk1 (47). Different pools of Cdk5RAP2 bind to either Cep68 or pericentrin, and centriole disengagement is promoted by Cdk5RAP2 release from both pools, either by Cep68 degradation or by pericentrin cleavage (47).…”

A new layer of degradation mechanism for PR-Set7/Set8 during cell cycle

“…61 Similarly, b-TRCP was reported to regulate centrosome separation partly via targeting CEP68 for degradation. 62 Interestingly, after exposure to UV irradiation, Securin is degraded by b-TRCP and results in cell cycle arrest. 63 Moreover, REST (repressor element-1-silencing transcription factor), which participates in cell cycle, is also degraded by b-TRCP.…”