Emerging insights into symmetry breaking in centriole duplication: updated view on centriole duplication theory

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Highlights

  • Plk4 can self-assemble into condensates.

  • Autonomous negative feedback of Plk4 restricts centriole duplication.

  • Self-organization of Plk4 may trigger symmetry breaking around the mother centriole.

  • After initial symmetry breaking of Plk4, the ring-to-dot conversion completes site selection for daughter centriole formation.

Centriole duplication occurs once per cell cycle. Since only a single daughter centriole is assembled adjacent to each mother centriole, symmetry around the mother centriole must be broken in the process of centriole duplication. Recent studies have established that Plk4, a master kinase for centriole duplication, can self-assemble into condensates, and have suggested that this Plk4 self-assembly is the key to symmetry breaking. Here, we present the current hypotheses for how Plk4 could break symmetry around the mother centriole via autonomous regulation. After this initial symmetry-breaking process, the ring-to-dot conversion of Plk4 around the mother centriole completes the selection of the site for procentriole formation. We also discuss how this dynamic transition contributes to the strict regulation of centriole duplication.

Introduction

The centriole is an essential organelle for centrosome assembly and cilia/flagella formation [1, 2, 3, 4]. Centriole duplication occurs once per cell cycle [5]. Importantly, only a single daughter centriole is formed next to the mother centriole. Dysregulation of centriole duplication has been observed in conditions such as cancer and microcephaly [2,6, 7, 8, 9]. So far, Plk4–STIL/Ana2–SAS6 proteins have been identified as evolutionarily conserved core factors for centriole duplication [1,10, 11, 12, 13, 14]. Loss of any one of these factors leads to a failure of centriole duplication, whereas overexpression results in centriole overduplication [14, 15, 16, 17, 18]. Plk4 acts upstream; loss of Plk4 or inhibition of its kinase activity results in defects in the recruitment and centriolar localization of STIL/Ana2 and SAS6 [17,19, 20, 21,22••].

In early G1 human cells, before STIL and HsSAS6 are recruited, Plk4 is initially distributed around the mother centriole in ring-like structures [19,21,23,24]. In the late G1 and S phases, Plk4 is distributed in a single focus around the mother centriole, and is colocalized with STIL and HsSAS6. This single focus, consisting of Plk4–STIL–HsSAS6, provides the assembly site for the new daughter centriole [19,21,23,24]. It has been proposed that the self-organization of Plk4 triggers symmetry breaking in the early stages of centriole duplication because, even before centriolar loading of STIL and HsSAS6, Plk4 is already arranged in asymmetrical ring-like structures around the mother centriole [19,21,22••]. However, it remains unclear how the activity and distribution of Plk4 are regulated during the symmetry-breaking process. In this review, we summarize recent findings regarding the self-organization properties of Plk4 and its autonomous regulation. We then discuss recent hypotheses for the mechanisms underlying symmetry breaking and subsequent site selection for centriole duplication.

Section snippets

Self-assembly of Plk4

Recent studies have revealed that Plk4 can self-assemble and form macromolecular condensates [22••,25••,26••]. Gouveia et al. showed that purified Xenopus Plk4 protein forms macromolecular condensates in vitro [25••]. Two groups reported that human Plk4 self-assembles into condensates both in vitro and in cells [22••,26••]. The key elements that promote the self-assembly of human Plk4 are thought to be its kinase activity and regions in Linker 1; the cryptic Polo-box domain (CPB), which

Autonomous negative feedback of Plk4 limits centriole duplication: concentration, activation and dissociation

In accordance with the accumulating knowledge regarding the self-regulation of Plk4, it would be reasonable to assume that the autonomous negative feedback system of Plk4 maintains the fidelity of centriole duplication (Figure 2). First, in G1, Plk4 localizes to the mother centriole by binding to the centriolar scaffolds Cep152 and Cep192 [23,24,36]. Subsequently, Plk4 can self-assemble on the surface of the scaffold proteins even in its inactive, non-phosphorylated state [22••]. It is

Emerging hypotheses for symmetry breaking in centriole duplication

In centriole duplication, Plk4 exhibits unique and dynamic behaviors [19,21,23,24,38••]. High resolution imaging has revealed that Plk4 adopts an asymmetrical ring-like distribution around the mother centriole before centriole duplication, and then undergoes a transition to a single focus corresponding to the single duplication site of the daughter centriole [19,21,23,24,38••]. It has been thought that this dynamic transition of Plk4 into a single focus is important for the prevention of

After symmetry is broken, STIL and HsSAS6 contribute to the dynamic ring-to-dot transition of Plk4

Plk4 undergoes a dynamic transition from an asymmetrical ring-like distribution to a single focus around the mother centriole during centriole duplication (Figure 3a) [19,23]. Although the knockdown of STIL and HsSAS6 suppresses the ring-to-dot transition of Plk4 [19,21,46], the roles of STIL and HsSAS6 in the dynamic Plk4 transition remain unclear. Considering the accumulating evidence and current knowledge, we postulate that the biochemical reactions underlying the initiation of centriole

Perspective

The initial observation of a pair of centrioles (mother and daughter) occurred over 140 years ago [56]. We are still in the process of understanding the precise mechanisms underlying the formation of a single daughter centriole per mother centriole. Strict regulation of the number of centriole copies is important for proper cell division and to prevent cancer development. Further consideration of the biochemical and biophysical aspects of this process is essential for understanding the

Conflict of interest statement

Nothing declared.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

This work was supported by a Grant-in-Aid for Scientific Research (S, 19H05651) from the Ministry of Education, Science, Sports and Culture of Japan, by Takeda Science Foundation, and by the Daiichi Sankyo Foundation of Life Science.

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    Present address: Interdisciplinary Research Institute of Grenoble, Laboratoire de Physiologie Cellulaire & Végétale, CEA, Grenoble 38054, France.

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