Centriole Reduplication during Prolonged Interphase Requires Procentriole Maturation Governed by Plk1

Abstract

Summary Supernumerary centrioles lead to abnormal mitosis [1,2] which in turn promotes tumorigenesis [3,4]. Thus, centriole duplication must be coordinated with the cell cycle to ensure that the number of centrioles in the cell doubles precisely during each cell cycle [5]. However, in some transformed cells centrioles undergo multiple rounds of duplication (reduplication) during prolonged interphase [6-8]. Mechanisms responsible for centriole reduplication are poorly understood. Here, we report that centrioles reduplicate consistently in cancerous and non-transformed human cells during G2 arrests and this reduplication requires the activity of Polo-like kinase 1 (Plk1). We also find that cell’s ability to reduplicate centrioles during S-arrests depends on the presence of activated (T210-phosphorylated) Plk1 at the centrosome. In the absence of activated Plk1, nascent procentrioles remain associated with mother centrioles, which prevent centriole reduplication. In contrast, if Plk1(pT210) appears at the centrosome, procentrioles mature, disengage from mother centrioles, and ultimately duplicate. Plk1 activity is not required for the assembly of procentrioles, however. Thus, the role of Plk1 is to coordinate centriole duplication cycle with the cell cycle. Activation of Plk1 during late-S-G2 induces procentriole maturation and after this point the centriole cycle can be completed autonomously, even in the absence of cell cycle progression.

Causes and consequences of centrosome abnormalities in cancer

“…Similarly, loss of the tumour suppressor BRAC1 leads to centrosome amplification via increasing the levels of the PCM component g-tubulin [73]. Re-duplication of centrioles can also be observed in cells during prolonged G2 arrest by a mechanism involving the maturation and premature disengagement of the procentrioles promoted by Plk1 [74]. Thus pathological conditions, such as persistent DNA damage, that may increase the time cells spend in G2, could contribute to centrosome amplification in cancer cells.…”

The Centrosome and Its Duplication Cycle

“…Inhibition of Plk1 in a Xenopus CSF extract, for example, will block disengagement in the presence of separase (Schockel et al 2011), and overexpression of Plk1 will promote centriole disengagement in G 2 (Loncarek et al 2010). It also seems that APC/C activity contributes to disengagement (Prosser et al 2012), and that Plk1 and APC/ C-Cdh1 activities can independently achieve this (Hatano and Sluder 2012).…”

“…The disengagement of the procentriole by Plk1 is hypothesized to expose a site on the mother, enabling it once again to be able to initiate formation of a new procentriole. At the same time, Plk1 is proposed to modify the daughter centriole in some way as to render it competent for the initiation for procentriole formation in the next cycle (Loncarek et al 2010;Wang et al 2011). …”

Small organelle, big responsibility: the role of centrosomes in development and disease

“…It is thus possible that centrosomal PD proteins prevent centriole overduplication, for instance by promoting engagement between the mother centriole and its procentriole [38,103,104]. Recent studies suggest that ORC1 exercises centrosome copy number control by suppressing CDK2-cyclin E-dependent reduplication of centrioles, a function specifically disrupted by Meier-Gorlin mutations in ORC1 [91].…”