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Centrosome biogenesis and function: centrosomics brings new understanding

Key Points

  • The centrosome is the major microtubule-organizing centre (MTOC) in eukaryotic cells, being comprised of two centrioles surrounded by an electron-dense matrix, the pericentriolar material (PCM). The capacity of the centrosome to organize microtubule (MT) arrays, such as the mitotic spindle, depends on its ability to nucleate, anchor and release MTs.

  • In many species, spindles can form without centrosomes owing to chromosome-mediated MT-nucleation pathways. However, in the absence of centrosomes, the fidelity of cell division is decreased and problems are observed in the context of specialized cell divisions, such as male meiosis and asymmetrical cell divisions. Centrosomes might also be important to regulate the G1–S transition.

  • In ciliated or flagellated cells, centrioles also function as basal bodies, structures anchored below the plasma membrane to seed axonemes, the MT-based structure of cilia and flagella. In recent years, evidence has accumulated for an indispensable role for cilia and flagella in various cellular and developmental processes, motility, propagation of morphogenetic signals in embryogenesis and sensory perception.

  • Centriole duplication ensures that each daughter cell inherits two centrioles. It proceeds in four consecutive steps: disengagement of the centrioles at the end of mitosis, nucleation of the daughter centrioles (also known as procentrioles before they acquire full centriolar length) in G1–S, elongation of the daughter centrioles (S and G2) and separation of the centrosomes (G2–M).

  • The recent availability of several complete genome sequences, together with advances in proteomics and functional genomics, has enabled the identification of both centriole components and putative regulatory molecules for the duplication cycle. This has revealed a strong evolutionary conservation of the molecules involved in centriole biogenesis. SAK/PLK4 (or ZYG-1 in Caenorhabditis elegans), SAS4, SAS6, centrin and γ-tubulin are conserved molecules that regulate centriole duplication. Overexpression of SAK/PLK4 and SAS6 leads to the amplification of MTOCs.

  • Recent studies have drawn attention to a group of molecules that inhibit the re-replication of DNA and might also be involved in inhibiting centriole reduplication. These results suggest a licensing mechanism for the regulation of centriole duplication: the cycle is divided into two stages, one during which duplication can start (licensing zone) and the other during which duplication only proceeds. This ensures that duplication occurs at the right time only. Separase, SAK/PLK4 and SAS6 have all been suggested as potential players.

  • Centrioles can also form de novo in the absence of a template. A view has emerged that there could be a universal mechanism for canonical, de novo and ciliogenic centriole formation. In all of these, procentrioles might be formed in the cytoplasm and be stabilized or catalysed by a mother centriole, or they might take longer to form if no centriole is present. It is clear that the assembly of centrioles de novo is inhibited by the presence of a single centriole.

Abstract

Centrosomes, which were first described in the late 19th century, are found in most animal cells and undergo duplication once every cell cycle so that their number remains stable, like the genetic material of a cell. However, their function and regulation have remained elusive and controversial. Only recently has some understanding of these fundamental aspects of centrosome function and biogenesis been gained through the concerted application of genomics and proteomics, which we term 'centrosomics'. The identification of new molecules has highlighted the evolutionary conservation of centrosome function and provided a conceptual framework for understanding centrosome behaviour and how it can go awry in human disease.

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Figure 1: Centriole and basal body structure.
Figure 2: The centriole duplication cycle.
Figure 3: Coordinating the two cycles: parallel mechanisms or shared controls?
Figure 4: Centriole biogenesis outside the centriole cycle.

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Acknowledgements

We apologize to colleagues whose work was not discussed or cited owing to space constraints. We are grateful for grants from Cancer Research UK, the Instituto Gulbenkian de Ciência, the Fundação para a Ciência e Tecnologia/ POCTI and for an International Joint Project Grant from the Royal Society for collaboration between the groups of M.B.D. and D.M.G. We thank R. Kuriyama, A. Rodrigues-Martins, N. Delgehyr and M. Bornens for discussions on the topic and comments on the manuscript. We also thank A. Hyman, T. Mueller-Reichert and J. Raff for sharing unpublished data. We also thank the reviewers for their suggestions, which improved this manuscript.

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Centrioles and derived structures: their functional significance (PDF 196 kb)

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Ciliary proteome database

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Glossary

Centrosome

The primary microtubule-organizing centre (MTOC) in animal cells. It is comprised of two centrioles surrounded by an electron-dense matrix, the pericentriolar material (PCM).

Microtubule

A hollow tube, 25 nm in diameter, formed by the lateral association of 13 protofilaments. Each protofilament is a polymer of α and β-tubulin subunits.

Centriole

The canonical centriole is a cylinder that is comprised of nine microtubule triplets, is 0.5 μm in length and has appendages at the distal ends upon maturation. There are variations of this structure, in which triplets are substituted by singlets or doublets and there are no appendages.

Basal body

A structure found at the base of eukaryotic cilia and flagella that organizes the assembly of the axoneme. Centrioles can give rise to basal bodies and vice versa. The structure of the basal body is the same as the one of the centriole; additionally, basal bodies have a transition zone at their distal end, which is contiguous with the axoneme.

Cilia

Microtubule-based membrane-surrounded cellular projections that extend up to 10 mm outwards from the cell. The majority of the cells in vertebrates have cilia. Cilia can serve as sensory organelles or, in the case of motile cilia, can move fluids around the cell. Motility is thought to depend on the structure of the axoneme, with most motile cilia displaying a 9C2 axoneme structure.

Flagella

Axoneme (9C2)-based cellular projections that help propel cells.

DNA licensing

A regulatory mechanism that divides the cell cycle into two phases: a licensed phase, during which initial steps for DNA replication are taken, but progression cannot take place; and an unlicensed state, during which the initial steps cannot be taken and progression takes place. This mechanism ensures that DNA replication occurs only once per cell cycle.

Pericentriolar material

Fibrillar material that surrounds centrioles in the centrosome that nucleates the growth of new microtubules.

Nucleus-associated body

The microtubule-organizing centre of D. discoideum is a nucleus-associated body that consists of a multilayered, box-shaped core embedded in an amorphous corona from which the microtubules emerge.

Coiled-coil

A region of low complexity formed by a number of α-helices wound around each other, which is common among structural and motor proteins. Coiled-coil domains are also involved in protein interactions.

Axoneme

The microtubule-based structure of cilia and flagella that gives them rigidity and the ability to move. It is a cylindrical structure comprised of nine pairs of doublet microtubules, arranged around a central pair of single microtubules (9C2). The central microtubules can be absent in non-motile cilia (9C0).

Spindle pole body

The microtubule-organizing centre of yeast and diatoms. It is a plaque-like structure that is embedded in the nuclear membrane. It nucleates microtubules both on the cytoplasmic and nuclear side.

Centriole disengagement

(also known as centriole disorientation). Both centrioles in the centrosome lose their orthogonal orientation towards each other at the end of mitosis and beginning of G1 phase. This event precedes new centriole formation.

Half-bridge

When a spindle pole body (SPB) is formed, it has a lateral structure, known as half-bridge. The half-bridge, like the SPB, is embedded in the nuclear envelope. This structure is the 'seed' for SPB duplication because the first step in duplication involves its elongation. Elongation leads to the deposition of satellite material that will expand into a duplication plaque, leading to the formation of a new SPB.

Cartwheel structure

A basal body precursor and one of the first structures to appear during basal body formation. It consists of a central hub and nine spokes, on top of which microtubules are added.

Kinetochore

A protein structure that assembles on the centromere during cell division and that links the chromosome to microtubules from the spindle.

SCF complex

A multisubunit ubiquitin ligase that targets proteins for degradation. It comprises SKP1, a member of the cullin family (CUL1), a RING-finger-containing protein (ROC1/RBX1) and an F-box-containing protein, which specifically recognizes certain substrates. Substrate recognition is enhanced following phosphorylation.

Deuterosome

A large electron-dense cytoplasmic organelle (75–400 nm diameter) that has a role in the formation of ciliary basal bodies.

Comparative genomics

The analysis and comparison of genomes from different species to gain a better understanding of how species have evolved and to determine the function of gene products and non-coding regions in the genome.

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Bettencourt-Dias, M., Glover, D. Centrosome biogenesis and function: centrosomics brings new understanding. Nat Rev Mol Cell Biol 8, 451–463 (2007). https://doi.org/10.1038/nrm2180

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