Centrosome Cycle

Abstract

Centrosomes are the major microtubule‐organising centres of animal cells. These small organelles participate in diverse cellular functions such as cell division, polarity, migration and signalling and are often deregulated in diseases such as cancer and microcephaly. Over the past two decades, technical advances enabled a deeper knowledge of the molecular composition and mechanisms of centrosome assembly and function. These progresses also allowed a better understanding on how the centrosome cycle is coordinated with the cell cycle to ensure that centrosomes duplicate once and only once. These discoveries together with the emergence of in vivo models of centrosome deregulation have consolidated the 100‐year‐old pioneer view of Theodor Boveri about the role of centrosome amplification (more than two centrosomes per cell) in abnormal cell division, tumorigenesis and developmental diseases such as microcephaly.

Key Concepts

  • Centrosomes are made of two orthogonally oriented centrioles surrounded by the pericentriolar material.
  • The ninefold symmetry of centrioles is mostly defined by the cartwheel, that is, the initial structure formed during centriole assembly made of SAS‐6 oligomers. This protein is highly evolutionarily conserved, being present in the last common ancestor of eukaryotes.
  • Centrosomes are not only the main microtubule organisers of animal cells but also actin‐organising centres.
  • Centriole duplication occurs only once per cell cycle and is triggered by a core module composed of PLK4‐SAS‐6‐STIL proteins. Regulation of the level of these components is critical to control centriole number in cells.
  • Centrosome duplication and cell cycle progression are tightly coupled and share common regulators.
  • Centrosome loss and amplification can lead to abnormal mitotic spindle formation, chromosome instability and cell cycle arrest.
  • Centrosome amplification leads to tumorigenesis and microcephaly.

Keywords: centrosome; centriole; MTOC; cell cycle; cell division; microtubule; cancer; microcephaly

Figure 1. Centrosome structure and functions. (a) Schematic representation of the ‘canonical’ mother–daughter centriole pair in most animal cells in 3D. Each centrosome comprises one mother (older) and one daughter (newly formed) centriole that are surrounded by a proteinaceous matrix (the pericentriolar material, PCM, depicted in blue) and centriolar satellites (electron‐dense cytoplasmic granules containing several centrosomal proteins, represented in grey). Centrioles are barrel‐shaped structures made of nine microtubule (MT) triplets and measure approximately 500 nm in height and 250 nm in diameter. Please note that only mother centrioles possess subdistal (pink) and distal (purple) appendages, which are important for cytoplasmic MTs docking and cilia formation, respectively. Centrosomes participate in many cellular processes such as cell proliferation, polarity, migration, sensing and signalling. (b) Schematic representations of longitudinal and cross sections of the centriole pair. The cartwheel, present only in daughter centrioles, is made of a 22‐nm central hub from which nine spokes emanate and the pinheads. The pinhead structure links the spokes to the A‐MT.
Figure 2. The centrosome cycle. During S phase, one procentriole forms perpendicularly to the proximal part of each preexisting centriole (Procentriole formation). Extra duplication rounds are inhibited until the following S phase. Procentriole elongation occurs between S phase and mitosis. At the end of G2 phase, centrosome accumulates more pericentriolar material (centrosome maturation) and separates (loss of the linker between the two centrosomes, yellow line). In mitosis, each centrosome migrates to opposite poles of the cell allowing proper spindle organisation. Finally, centrioles disengage during anaphase.
Figure 3. Major regulators of centriole biogenesis. The initiation of centriole biogenesis starts with the recruitment of PLK4 at the procentriole nucleation site. This process is dependent on CEP63, CEP152 and CEP192 in humans and allows SAS‐6 and STIL recruitment and maintenance at centrioles, therefore enabling cartwheel formation. SAS‐6 and STIL are essential for CPAP recruitment to the centriole, with the latter being thought to induce MT incorporation to centrioles. Subsequently, procentriole elongation is promoted mostly by CPAP, CEP120 and CEP135 and restricted by CP110‐CEP97.
Figure 4. Centrosome amplification and diseases. Centrosome abnormalities, for example, centrosome amplification (more than two centrosomes per cell), are involved in several diseases such as microcephaly and cancer. Supernumerary centrosomes might trigger tumour formation by promoting chromosomal instability and/or invasiveness. Centrosome amplification might cause microcephaly by diminishing the neural stem cell pool.
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Further Reading

Bettencourt‐Dias M, Hildebrandt F, Pellman D, et al. (2011) Centrosomes and cilia in human disease. Trends in Genetics: TIG. 27 (8): 307–315.

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The Centrosome Renaissance (2014) Special theme issue of Philosophical Transactions B from the Royal Society.

Vertii A, Hehnly H and Doxsey S (2016) The centrosome, a multitalented renaissance organelle. Cold Spring Harbor Perspectives in Biology 8 (12). pii: a025049.

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Marteil, Gaëlle, and Bettencourt‐Dias, Mónica(Nov 2017) Centrosome Cycle. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001362.pub2]