The centrosome duplication cycle in health and disease

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The centrosome duplication cycle in health and disease

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Erich A. Nigg ⇑, Lukáš Cˇajánek, Christian Arquint Biozentrum, University of Basel, Klingelbergstrasse 50/70, CH-4056 Basel, Switzerland

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Article history: Received 22 April 2014 Revised 6 June 2014 Accepted 7 June 2014 Available online xxxx Edited by Wilhelm Just

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Keywords: Centriole Centrosome Plk4 Cancer STIL Microcephaly

a b s t r a c t Centrioles function in the assembly of centrosomes and cilia. Structural and numerical centrosome aberrations have long been implicated in cancer, and more recent genetic evidence directly links centrosomal proteins to the etiology of ciliopathies, dwarfism and microcephaly. To better understand these disease connections, it will be important to elucidate the biogenesis of centrioles as well as the controls that govern centriole duplication during the cell cycle. Moreover, it remains to be fully understood how these organelles organize a variety of dynamic microtubule-based structures in response to different physiological conditions. In proliferating cells, centrosomes are crucial for the assembly of microtubule arrays, including mitotic spindles, whereas in quiescent cells centrioles function as basal bodies in the formation of ciliary axonemes. In this short review, we briefly introduce the key gene products required for centriole duplication. Then we discuss recent findings on the centriole duplication factor STIL that point to centrosome amplification as a potential root cause for primary microcephaly in humans. We also present recent data on the role of a disease-related centriole-associated protein complex, Cep164-TTBK2, in ciliogenesis. Ó 2014 Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies.

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1. Introduction Centrosomes are the major microtubule organizing centers of animal cells [1–4]. Each centrosome usually comprises two centrioles embedded in a pericentriolar protein matrix (PCM). Centrioles are barrel-shaped structures that, in human cells, are made up of triplet microtubules. The older of the two centrioles, often referred to as the ‘mature’ centriole, carries distal and subdistal appendages, and the two centrioles can be distinguished by staining for marker proteins [5–8]. In most species, centriole biogenesis involves the early formation of a so-called cartwheel at the base of the nascent centriole [4]. One major evolutionarily conserved component of the cartwheel is the coiled-coil protein SAS-6 [9–11]. As demonstrated by beautiful structural studies, SAS-6 imparts the typical nine-fold symmetry to the centriole [12–16]. Importantly, centrioles function not only as important building blocks for centrosome assembly [17], but also as crucial organelles in ciliogenesis. In fact, in most quiescent cells the mature centriole gets anchored underneath the plasma membrane, where it triggers the formation of a single, axoneme-containing cilium [18]. This socalled primary cilium is non-motile but functions as an antennalike receiver for chemical and mechanical signals [19]. The PCM was long considered an amorphous structure, but recent super-resolution microscopy has revealed a considerable degree

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⇑ Corresponding author. Fax: +41 61 267 2098. E-mail address: [email protected] (E.A. Nigg).

of organization amongst various coiled-coil proteins [20–23]. One major function of the PCM is to recruit c-tubulin ring complexes that are in turn required for microtubule nucleation [24]. In addition, it is widely held that centrosomal PCM recruits various signaling components, thereby acting as a solid-state platform to enhance and integrate intracellular signal transduction [25–27]. Early studies in the nematode Caenorhabditis elegans had identified five genes as being critical for centriole biogenesis: ZYG-1, SPD2, SAS-4, SAS-5, SAS-6. Furthermore, the corresponding proteins were shown to act sequentially, with Spd-2 being important for the recruitment of the Zyg-1 kinase, followed by the association of SAS-5/SAS-6 and the SAS-4-mediated assembly of microtubules [28]. Although it was initially difficult to identify homologs of these proteins in non-nematode species, subsequent studies have demonstrated the existence of structural or functional counterparts also in other organisms, both invertebrates and vertebrates (Table 1). In particular, a distant member of the Polo kinase family, Plk4 (Polo-like kinase 4), was discovered as a key regulator of centriole biogenesis in both human cells and Drosophila [29–31]. Depletion of this kinase from proliferating cells causes loss of centrioles, and, conversely, overexpression of Plk4 triggers the near-simultaneous formation of multiple daughter centrioles. In most cells analyzed to date, Plk4 is a very low abundance protein, due to its propensity to dimerize and trans-autophosphorylate, which then triggers the recruitment of the ubiquitin ligase b-TrCP, followed by proteasome-mediated degradation [32–36]. In addition to the evolutionarily conserved centriole duplication factors first

http://dx.doi.org/10.1016/j.febslet.2014.06.030 0014-5793/Ó 2014 Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies.

Please cite this article in press as: Nigg, E.A., et al. The centrosome duplication cycle in health and disease. FEBS Lett. (2014), http://dx.doi.org/10.1016/ j.febslet.2014.06.030

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identified in C. elegans, additional gene products were found to be important for centriole biogenesis in Drosophila [37,38] and/or human cells [31,39]. Thus, complementing the evolutionarily conserved core mechanism for centriole duplication, a number of species-specific extensions and variations have been observed. Conversely, some of the core factors originally identified in C. elegans are not essential in all species. For example, no Spd-2 homolog is present in the planarian Schmidtea mediterranea and the parasite flatworm Schistosoma mansoni, even though these species form centrioles [40]. Thus, Spd-2 may generally be more important for PCM assembly than centriole formation per se. In support of this view, the Drosophila homolog of Spd-2 is clearly important for PCM recruitment but dispensable for centriole duplication [41,42]. Also, whilst Spd-2 recruits the Zyg-1 kinase in C. elegans, a structurally distinct protein, Asterless, is critical for Plk4 recruitment in Drosophila [43]. In human cells, the recruitment of Plk4 to centrioles is accomplished through joint efforts of the Spd-2 and Asterless homologs, the proteins Cep192 and Cep152, respectively [44,45]. This readily explains why both proteins are required, albeit to different degrees, for the maintenance of correct centriole numbers in human cells. As our understanding of the molecular details of centriole biogenesis progresses, additional species- and cell typespecific differences will undoubtedly be uncovered. Our current understanding of the mechanisms underlying centriole biogenesis in proliferating cells, as well as in multiciliated epithelial cells, has been described in excellent recent reviews [4,46]. Likewise, authoritative reviews covering the importance of centrioles for ciliogenesis and the impact of ciliary dysfunction on human health are available [2,18,19,47,48]. In the following, we will briefly discuss the implications of centrosome aberrations for cancer and then focus on two recent studies from our laboratory that relate to microcephaly and ciliopathies/spinocerebellar ataxia, respectively.

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2. Centrosome aberrations in cancer

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Several decades prior to the discovery of oncogenes and tumor suppressor genes, Theodor Boveri (1862–1915) proposed that Table 1 Major centriole duplication factors. Caenorhabditis elegans

Drosophila melanogaster

Homo sapiens

(A) Core components Spd-2 Zyg-1 SAS-5 SAS-6 SAS-4

DSpd-2⁄ Plk4 (Sak) Ana-2 DSAS-6 DSAS-4

Cep192+ Plk4 (Sak) STIL HsSAS-6 CPAP

(B) Additional components ⁄

DBld10 DCP110⁄ Centrobin⁄ Asterless Poc1

Cep135 CP110 Centrobin Cep152 hPoc1 hPoc5 Spice Cep120 Cep63 Cep97 Cep76 Centrins+

Ana1 This table lists major proteins implicated in centriole duplication in the indicated species, but we emphasize that the list is not meant to be comprehensive. Also, we apologize for incomplete referencing, caused by editorial restrictions on citations. Proteins marked by ⁄ do not necessarily play essential duplication roles in all species; for example, DSpd-2, DCP110, DBld10 and Centrobin are not required for duplication in Drosophila [8,41,111–113]. In other cases – proteins marked by + – controversial data have been reported [31,114–117].

tumors develop as a consequence of chromosomal imbalances, and, furthermore, suggested that centrosome aberrations constitute one prominent root-cause of such imbalances [49]. While the fundamental importance of mutations and genetic imbalances for tumorigenesis is well established, the impact of centrosome aberrations on tumor development continues to be a subject of debate. On the one hand, many human tumors carry extensive centrosome aberrations, and there is a strong correlation between the extent of these aberrations and the clinical aggressiveness of tumors [50–52]. On the other hand, direct genetic evidence to support the involvement of any particular centrosomal gene product in carcinogenesis remains scarce [53]. Most tumors carry both numerical and structural centrosome aberrations and it is difficult, therefore, to disentangle the physiological consequences of these aberrations. However, from a conceptual perspective it is interesting to consider the two types of aberrations separately. Numerical aberrations, most commonly excessive numbers of centrioles, have been studied extensively, both with regard to their origin and their consequences. Prominent causes for ‘supernumerary’ centrioles are overduplication or division failure. Overduplication may reflect loss of either cell cycle control or copy number control [54], whereas division failure results in a centriole amplification that is accompanied by an increase in ploidy [55]. In short-term cell culture experiments, the two mechanisms can readily be distinguished by staining of extra centrioles with antibodies against centriolar appendage proteins [56]. The consequences of centriole amplification have also been examined in considerable mechanistic detail. As already noticed by Boveri, excessive numbers of centrioles frequently results in the formation of multipolar spindles [49]. However, live cell imaging has revealed that multipolar spindles do not inevitably lead to multipolar divisions, and when they do, the resulting progeny is rarely (if ever) viable [57–59]. Instead, evidence has been reported for occasional inactivation of supernumerary centrosomes [58,60,61]. In addition, many cells use centrosome-independent spindle assembly mechanisms to cluster extra centrosomes, so that supernumerary centrosomes coalesce to allow the formation of bipolar spindles [60,62–64]. These clustering mechanisms are important not only to allow the survival of cells with multiple centrosomes, but they also constitute a common cause of chromosome segregation errors [57,59]. Thus, it remains attractive to postulate that numerical centriole aberrations constitute an important source of chromosomal instability in tumor cells. Much less attention has so far been focused on structural centrosome aberrations. This is perhaps unfortunate, as, a priori, structural centrosome aberrations may well have a profound impact on cytoskeletal organization, and hence on cell shape, polarity and motility. Structural centrosome aberrations commonly reflect deregulated expression and/or posttranslational modification (notably phosphorylation) of centrosomal proteins [52,65]. Excess centrosomal protein often associates primarily with the resident centrosome; in addition, formation of centrosome-related bodies (CRBs) – extra-centrosomal assemblies devoid of centrioles – is commonly observed [66,67]. Depending on the functional properties of the centrosomal proteins that are deregulated in any particular tumor cell, notably their ability to interact with c-tubulin ring complexes, intracellular microtubule nucleation is expected to be either enhanced or suppressed, with potentially profound consequences for cell shape, polarity and motility [66]. In turn, these parameters have the potential to affect the clinical behavior of tumor cells, including their propensity to metastasize. Another area that undoubtedly warrants additional exploration concerns the relationship between ciliogenesis and cancer. Aberrations in centriole numbers and/or centrosome structure are expected to influence the number, timing of formation and disassembly, disposition and function of cilia [68,69]. Thus centriolar

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and centrosomal aberrations hold the potential to profoundly affect signal transduction pathways that operate through cilia.

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3. Microcephaly: could centriole amplification represent a root cause?

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While genetic data supporting a causal role of centrosome aberrations in cancer progression remains scarce, there is ample evidence to directly link a set of centrosomal proteins to neurodevelopmental disorders and dwarfism. In particular, 10 out of 13 genes implicated in autosomal recessive primary microcephaly (MCPH) code for proteins that were found to localize to centrosomes and/or the mitotic spindle pole (Table 2); in addition, mutations affecting some centrosomal proteins have been linked to dwarfism [70]. These findings raise the question of how mutations in genes coding for centrosome- or spindle pole associated proteins can lead to small brains and/or bodies. Whilst this question remains to be answered for any of the reported cases of MCPH, effects of centrosome aberrations on asymmetric cell division feature prominently amongst the proposed mechanisms [71,72]. In particular, it has been considered that inappropriate spindle positioning may impair the normal balance between stem cells and progeny. A priori, there is no reason to assume that all MCPH mutations cause reduced brain size through a single common mechanism. Therefore, it will clearly be important to directly examine the physiological consequences of mutations in particular MCPH genes. In our laboratory, we have characterized the physiological function of STIL [73,74]. STIL attracted our interest for several reasons. First, early studies had revealed that STIL is essential for embryonic development in both mouse and zebrafish [75,76]. Subsequently, mutations in STIL (also known as MCPH7; see Table 2) were identified in patients afflicted by primary microcephaly [77]. Then, sequence comparisons identified STIL as a candidate vertebrate homolog of the key centriole duplication factors SAS-5 in C. elegans and Ana2 in Drosophila [78]. In line with this proposal, STIL was found to be indispensable for centriole duplication in vertebrate cells, whilst transient (substantial) overexpression of STIL caused centriole amplification [73,79–81]. Furthermore, co-localization of STIL and SAS-6 at the proximal ends of nascent centrioles suggested that the two proteins cooperate in cartwheel formation, and interactions between STIL and CPAP/hSAS-4 have also been revealed [80–83]. Finally, STIL has been identified as a target gene for E2F transcription factors [84], suggesting that STIL may represent an important element in the regulation of the centriole duplication cycle by the Retinoblastoma (pRb) pathway [85].

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Table 2 Genes implicated in MCPH.

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Protein name

Localization

MCPH1 MCPH2 MCPH3 MCPH4 MCPH5 MCPH6 MCPH7 MCPH8 MCPH9 MCPH10 MCPH11 MCPH12 SCKL6

Microcephalin WDR62 CDK5RAP2/Cep215 CASC5 ASPM CPAP/CENPJ STIL CEP135 CEP152 ZNF335 PHC1 Cdk6 Cep63

Centrosome Centrosome Centrosome Kinetochore Centrosome Centrosome Centrosome Centrosome Centrosome Nucleus Nucleus Centrosome (?) Centrosome

This table was adapted from [118]; mutations in Cep63 (SCKL6) have been identified in patients with a combination of MCPH and growth retardation (mild seckel syndrome) by Gergely and coworkers [119].

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Intrigued by the observation that levels of STIL are critical for maintenance of correct centriole numbers, we explored the cell cycle regulation of STIL levels by live cell imaging [74]. We found that STIL levels progressively increased as cells approached mitosis and then dropped at mitotic exit, so that STIL was virtually undetectable at the end of cell division. Remarkably, this mitotic regulation involved two steps, affecting two distinct pools of STIL. Beginning during prometaphase, STIL dissociated from mitotic centrosomes. This first step was dependent on Cyclin-dependent kinase 1 (Cdk1) and most likely reflects direct phosphorylation of STIL. This finding has interesting implications for the mechanism and timing of cartwheel disassembly. The second step, the ubiquitin-dependent degradation of cytoplasmic STIL, began only after the onset of anaphase. In line with earlier observations [73,81,86], this step was dependent on the anaphase-promoting complex/cyclosome (APC/C), a prominent cell cycle-regulatory ubiquitin-ligase [87,88]. We then discovered that an evolutionarily conserved KEN box motif, close to the C-terminus of STIL, is critical for STIL degradation [74]. Remarkably, this critical KEN box was predicted to be missing in mutant versions of STIL (referred to as p.Val1219X and p.Gln1239X) that had previously been described in MCPH patients [77]. We confirmed that these MCPH versions of STIL resisted APC/C induced degradation, resulting in progressive accumulation of the protein. In turn, and most importantly, the accumulation of MCPH mutant STIL triggered centriole amplification, indicating retention of full functionality with regard to centriole biogenesis (Fig. 1). Previously, it has generally been assumed that MCPH-associated mutations result in functional impairment of the respective centrosomal proteins [89]. However, considering that elimination of the STIL gene causes embryonic lethality, both in the mouse [75] and in zebrafish [76], it seemed unlikely that complete loss of STIL functionality would be tolerated in humans. Moreover, the KEN-box deficient STIL proteins discussed here clearly display a gain-of-function phenotype, at least when assayed in cell culture [73,80]. So, how could one reconcile the observed gain-of-function phenotype associated with MCPH mutants of STIL in cell culture [74,80] with the recessive inheritance of the disease in human patients [77]? One possible explanation relates to the oligomerization of STIL. Assuming that wildtype STIL and MCPH mutant STIL are able to oligomerize when co-expressed, we consider it likely that some degree of cell cycle-dependent degradation will be conferred upon MCPH STIL by STIL WT present in the oligomer. Thus, in heterozygous individuals STIL levels may not rise sufficiently fast to cause disease. In contrast, loss of the wild-type allele would allow the stabilizing effect of the KEN-box deficient MCPH allele to cause full expression of the centriole amplification phenotype. This, we believe, could explain the observed recessive inheritance of a disease caused by a functionally dominant allele. Could the centriole amplification caused by the KEN-box deficient STIL mutants stay at the root of microcephaly in the corresponding patients? Strong support for this possibility stems from recent independent work in mice. Centriole amplification has so far been studied mainly from the perspective of a potential impact on carcinogenesis, and little attention has been attributed to a possible link between this phenotype and microcephaly. Yet, overexpression of the key centriole duplication kinase Plk4 in developing mouse brains was recently shown to cause not only centriole amplification, but also a phenotype resembling microcephaly [90]. Although mutations in Plk4 have not been observed in human microcephaly patients, the parallels between the results observed in this mouse model and those observed in cells harboring a MCPH mutant version of STIL are striking. Together, they suggest that centriole amplification might well constitute a root cause of microcephaly. In support of this view, we note that extra centrioles have

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Fig. 1. Expression of MCPH STIL mutant proteins cause formation of multipolar spindles (due to centriole amplification). Human U2OS cells carrying STIL WT or STIL MCPH mutant transgenes were fixed and stained for immunofluorescence microscopy, using antibodies to stain alpha-tubulin (green) and the centrosome marker Cep135 (red). DNA is depicted in blue. Images on the right show spontaneously occurring mitotic cells; scale bar: 5 lm. Schemes to the left indicate the action of the APC/C-proteasome pathway on STIL. (A) STIL WT contains a C-terminal KEN box that is required for its APC/C-mediated degradation at the end of mitosis. Cell cycle control of STIL levels ensures correct centrosome numbers – and hence spindle bipolarity – in proliferating cells. (B) Truncation mutations in STIL (e.g. p.Val1219X) from microcephaly patients delete the KEN box, conferring resistance to degradation of STIL. The ensuing elevated levels of STIL cause supernumerary centrosomes, which occasionally trigger spindle multipolarity.

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been described in patients harboring mutations in microcephalin (MCPH1), Cep135 (MCPH8) and Cdk5rap2 (MCHP3) [91–93]. The proposed hypothesis raises the question of how centriole amplification could affect brain size? Previously, centrosome aberrations were thought to affect brain development through effects on asymmetric division, deregulating the balance between stem cells and progenitors [71]. In this context it is interesting that the centrosome amplification caused in mouse brains by overexpression of Plk4 did not significantly disturb spindle orientation but instead triggered apoptosis, presumably as a consequence of aneuploidy [90]. Thus, the induction of cell death by centriole amplification may represent a straightforward mechanism for reducing cell number in developing brains. This being said, there is no reason to expect that all forms of centrosome-related MCPH arise through similar molecular mechanisms [71,72,94]. For example, a mutation in CPAP (E1235V) lowers the affinity of this protein towards STIL, and this is predicted to partially interfere with centriole duplication [81–83,95]. Other MCPH-related proteins are likely to regulate mitotic spindle orientation [96] or function in DNA damage response pathways [91,97]. While it is plausible that perturbation of DNA damage responses will impair cell viability, it is intriguing that some of these conditions also cause centriole amplification [98]. In future, it will clearly be interesting, therefore, to ask which of the many described MCPH mutations cause an increase or decrease in centriole numbers. 4. A centriolar protein complex linked to renal ciliopathies and spinocerebellar ataxia A key role in ciliogenesis resides with specialized structures, termed appendages, at the distal ends of mature centrioles (basal bodies) [99,100]. A prominent marker for this structure is the

protein Cep164, first identified in a screen for components that are essential for ciliogenesis [101]. The gene coding for Cep164 was subsequently shown to be mutated in patients afflicted by renal ciliopathies [102]. How exactly Cep164 functions in ciliogenesis remains to be fully understood, but recent studies point to distinct roles for the C- and N-terminal parts of this protein. While the C-terminal part has been implicated in the recruitment of ciliary vesicles [103], our recent studies suggest that a main function of the N-terminal part of Cep164 relates to the recruitment of a protein kinase, Tau tubulin kinase 2 [104]. This member of the casein kinase I family was first identified for its ability to phosphorylate the microtubule-associated protein Tau [105] and subsequently found to be mutated in spinocerebellar ataxia type 11 [106]. Intrigued by the observation that the phenotypes observed upon siRNA-mediated depletion of Cep164 closely resembled those seen in a mouse carrying a TTBK2 mutation [107], we explored the possibility that these two proteins might form a complex. Our findings lead us to conclude that the two proteins indeed interact at centrioles and that Cep164 is phosphorylated by TTBK2 [104]. Mapping studies revealed that the interaction depends on a WW motif within the N-terminal part of Cep164 and involves the C-terminal non-catalytic end domain of TTBK2. Most strikingly, chimeric constructs in which the catalytic domain of TTBK2 was fused to the centriole-targeting C-terminal domain of Cep164 largely rescued the ciliogenesis defects of Cep164-depleted cells [104]. Taken together, these experiments argue that one main function of Cep164 consists in the recruitment of TTBK2 to the distal appendages of centrioles. In future experiments it will be important to unravel how TTBK2 promotes ciliogenesis and identify the physiological substrates of this kinase. From the perspective of human disease, the question arises of why mutations in Cep164 lead to nephronophthisis-related ciliopathies [102], while mutations in TTBK2 cause spinocerebellar ataxia [106]. Clearly, much remains to be learned about the assembly and regulation of distal appendages [39,108–110]. This in turn will hopefully set the stage for a better understanding of the molecular functions of the Cep164–TTBK2 complex and the role of these proteins in the etiology of human disease.

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Acknowledgments

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We thank Jordan Raff (Oxford Univ.) and all members of the Nigg laboratory for helpful discussions. Work in the author’s laboratory was supported by the University of Basel and the Swiss Q3 National Science Foundation (grant 310030B_149641/1). C.A. Q5 acknowledges a Ph.D. fellowship from the Werner Siemens-Foundation (Zug, Switzerland). L.C. was supported by a long-term fellowship from FEBS.

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Please cite this article in press as: Nigg, E.A., et al. The centrosome duplication cycle in health and disease. FEBS Lett. (2014), http://dx.doi.org/10.1016/ j.febslet.2014.06.030

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