See online version for legend and references.188 Cell 136, January 9, 2009 ©2009 Elsevier Inc. DOI 10.1016/j.cell.2008.12.035

SnapShot: Centriole BiogenesisMónica Bettencourt-Dias1 and David M. Glover2

1Instituto Gulbenkian de Ciência, Oeiras, Portugal; 2University of Cambridge, Cambridge, UK

Protein Phenotype when disrupted

PC

m R

ecru

itm

ent

and

dup

licat

ion

SPD2 (Ce, Dm)/CEP192 (Hs)

No centriole duplication (Ce); <PCM recruited (Ce, Dm, and Hs); no basal body duplication (Dm)

Asterless (Dm)/CEP152 (Dr, Hs)

Aberrant PCM recruitment (Dm) and centriole duplication (Dm and Dr)

γ-Tubulin (Dm, Hs, Tt, Pt)/TBG (Ce)

Aberrant centriole duplication (Ce, Hs, Tt), centriole structure and separation (Pt, Dm)

Overexpression: de novo formation, amplifi cation of basal bodies (Tt)

Trig

ger

s o

f B

iog

enes

is

SAK/PLK4 (Dm, Hs) No duplication (Dm, Hs); no reduplication (Hs); no formation of basal bodies (Dm)

Overexpression: amplifi cation (Dm, Hs); de novo formation (Dm)

ZYG1 (Ce) No duplication

ess

enti

al m

ole

cule

s fo

r C

entr

iole

Bio

gen

esis

SAS6 (Ce, Hs)/DSAS6 (Dm)/Bld12 (Cr)

No duplication (Hs, Dm, Ce); no reduplication (Hs)

Overexpression: amplifi cation (Dm, Hs)

SAS4 (Ce)/DSAS4 (Dm)/CPAP(Hs)

No duplication (Hs, Ce, Dm, Cr); no reduplication (Hs)

SAS5 (Ce) No duplication

CP110 (Hs)/DCP110 (Dm)

No duplication (Dm); no reduplication or amplifi cation (Hs)

Centrin (Hs)/Cdc31 (Sc, Sp)/VLF2 (Cr)/CEN2/3 (Pt)/CEN1 (Tt)

No duplication (Sp, Sc, Tt); differing duplication results (Hs); aberrant centriole segregation (Cr), aberrant duplication geometry (Pt)

SFL1 (Sc) No SPB duplication

δ-Tubulin (Hs); δ-PT1 (Pt); UNI3 (Cr)

Centrioles with fewer C tubules (Cr, Pt)

ε-Tubulin (Xl, Hs, Pt); Bld2(Cr)

Centriole stability disrupted, singlets (Cr); no duplication (Xl, Pt); aberrant PCM organization (Xl)

Ana1 (Dm) No duplication

Ana2 (Dm) No duplication

Ana3 (Dm) No duplication

Centrobin (Hs) No duplication

Cep135 (Hs)/BLD10 (Cr)/DBld10 (Dm)

No amplifi cation upon SAK/PLK4 overexpression (Hs); no duplication (Dm); disorganized microtubules (Hs); no basal body duplication (Cr)

Overexpression: accumulation of particles (Hs)

Cel

l-C

ycle

Reg

ulat

ors

CDK2 (Hs, Xl, Gg) No reduplication, normal duplication, needed for duplication in absence of CDK1

Separase (Xl) No centriole disengagement, impaired duplication

Spliced Sgo1 (Mm) Precocious centriole disengagement

p53 (Mm, Hs) Amplifi cation

CHK1 (Gg, Hs) No centrosome amplifi cation upon DNA damage

PLK1 (Hs) No reduplication in S phase-arrested cells

PLK2 (Hs) No reduplication in S phase-arrested cells

MPS1 (Hs, Mm, Sc) No reduplication (Hs, Mm; reports differ); normal duplication (Dm); no spindle-pole-body duplication

BRCA1 (Hs, Mm) Premature centriole separation and reduplication in S-G2 boundary (Hs); amplifi cation (Mm)

Cdc14B (Hs) Amplifi cation

PP2 (Dm) Centrosome amplifi cation

Overexpression: prevents reduplication

Nucleophosmin/B23 (Mm, Hs)

Amplifi cation

CAMKII (Xl) Blocks early steps in duplication

CDK1 (Dm, Sc) Amplifi cation

Skp1, Skp2, Cul1, Slimb (SCF Complex) (Dm, Xl, Mm, Hs)

Blocks separation of M-D pairs and reduplication (Xl); increased centrosome number (Dm, Mm)

Geminin (Hs) Centrosome amplifi cation

Overexpression: blocks reduplication

SnapShot: Centriole BiogenesisMónica Bettencourt-Dias1 and David M. Glover2

1Instituto Gulbenkian de Ciência, Oeiras, Portugal; 2University of Cambridge, Cambridge, UK

188.e1 Cell 136, January 9, 2009 ©2009 Elsevier Inc. DOI 10.1016/j.cell.2008.12.035

Centrioles, Centrosomes, and CiliaThe centrosome is the primary microtubule-organizing center (MTOC) in animal cells. It regulates cell motility, adhesion, and polarity during interphase of the cell cycle and facilitates the organization of the spindle poles during mitosis. The centrosome comprises two centrioles that are surrounded by an electron-dense and protein-rich matrix called the pericentriolar material (PCM). The canonical centriole has nine microtubule (MT) triplets and is ~0.5 µm long and 0.2 µm in diameter. The mother centriole has subdistal and distal appendages, which dock cytoplasmic MTs and may anchor centrioles to the cell membrane to serve as basal bodies. Basal bodies seed the growth of the axoneme, the structure that confers rigidity and motility to cilia and flagella. Cilia and flagella play critical roles in physiology, development, and disease. Most motile cilia display axonemes that have 9 doublets and 1 central pair (A), whereas nonmotile, primary cilia display 9 doublets with no central pair (B). Abnormalities in centrosomes occur in many types of cancer and can be associated with genomic instability. This is due to the fact that supernumerary and often irregular centrosomes can result in aberrant cell division as well as abnormalities during asymmetric cell division.Centriole BiogenesisComponents of the PCM, such as γ-tubulin, may play a role early in the process of centriole biogenesis. SAK/PLK4, a protein kinase of the Polo-like protein kinase family, is essential for centriole biogenesis in flies and in human cells. This kinase is also known to be mutated in hepatocellular carcinomas; mice that have only one copy of the gene encoding SAK/PLK4 are more prone to develop cancer. Overexpression of SAK/PLK4, or suppression of its degradation by the SCF/Slimb complex, leads to an increase in the number of centrioles, with each mother centriole being able to nucleate more than one daughter centriole at a time. Most strikingly, this kinase can trigger centriole formation de novo in Drosophila eggs or tissue culture cells depleted of centrioles.The first described intermediate showing nine-fold symmetry in centriole assembly is the cartwheel. Bld10/CEP135 and SAS6 are two essential components of the cartwheel. Mutations in those molecules most often result in failure to form centrioles or formation of centrioles with abnormal symmetry. Assembly and stabilization of centriole MTs are dependent on SAS4 and γ-tubulin. Posttranslational modification of MTs may also play a role. Another component, CP110, may be essential for capping the centriolar structure to regulate its length and function. Bld10, SAS6, and SAS4 all act downstream of SAK/PLK4 in canonical centriole biogenesis. SAS6 and SAS4 are also required downstream of SAK/PLK4 in de novo centriole formation, suggesting a unique pathway for centriole biogenesis triggered by SAK/PLK4.The Centrosome CycleThe number of centrioles in a cell is controlled through a canonical duplication cycle that is coordinated with the chromosome duplication cycle. CDK1, CDK2, and Separase, among others proteins, may play a role in coordinating the two cycles. During centriole duplication, one new centriole (daughter) forms orthogonally to each existing centriole (mother) in a conservative fashion, once per cell cycle. Four consecutive steps in the centrosome cycle have been defined through electron microscopy: disengagement of the centrioles, nucleation of the daughter centrioles, elongation of the daughter centrioles, and separation of the centrosomes. Disengagement of centrioles is coordinated with chromatid segregation during mitotic exit and is required for duplication in the next cycle. Nucleation of daughter centrioles is coordinated with DNA synthesis, whereas centrosome separation occurs during G2 phase of the cell cycle. When the cell enters mitosis, it is equipped with two centrosomes that then participate in mitotic spindle assembly. SAS6 and SAK/PLK4 are tightly regulated during the cell cycle to prevent centriole amplification.

AbbreviationsPCM, pericentriolar material; RNAi, RNA interference; M-D, mother-daughter.Reduplication refers to centrosome amplification in the context of cells arrested during S phase. Ce, Caenorhabditis elegans; Cr, Chlamydomonas reinhardtii; Dm, Drosophila melanogaster; Hs, Homo sapiens; Mm, Mus musculus; Pt, Paramecium tetraurelia; Sc, Sac-charomyces cerevisiae; Sp, Schizosaccharomyces pombe; Tt, Tetrahymena thermophila; Gg, Gallus gallus; Dr, Danio rerio; Xl, Xenopus laevis.

ACknowledgmenTs

We thank Z. Carvalho-Santos, A. Rodrigues-Martins, I. Cunha-Ferreira, and I. Bento for help with the figure.

RefeRenCes

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