CEP152 is a genome maintenance protein disrupted in Seckel syndrome

Kalay, Ersan; Yiğit, Gökhan; Aslan, Yakup; Brown, Karen E.; Pohl, Esther; Bicknell, Louise S.; Kayserili, Hülya; Li, Yun; Tüysüz, Beyhan; Nürnberg, Gudrun; Kieß, Wieland; Koegl, Manfred; Baessmann, Ingelore; Buruk, Kurtulus; Toraman, Bayram; Kayıpmaz, Saadettin; Kul, Sibel; İkbal, Mevlit; Turner, Daniel J.; Taylor, Martin S.; Aerts, Jan; Scott, Carol; Milstein, Karen; Dollfus, Hélène; Wieczorek, Dagmar; Brunner, Han G.; Hurles, Matthew E.; Jackson, Andrew P.; Rauch, Anita; Nürnberg, Peter; Karagüzel, Ahmet; Wollnik, Bernd

doi:10.1038/ng.725

Cited by 205 publications

(232 citation statements)

References 15 publications

Supporting

Mentioning

225

Contrasting

Unclassified

Order By: Relevance

“…In contrast to other microcephaly or Seckel cells that display numerically aberrant centrosomes, cells in the current study displayed correct numbers of centrosomes and mitotic spindle poles (Fig 1A; Rauch et al , 2008; Kalay et al , 2011; Hussain et al , 2012; Martin et al , 2014). However, interphase centrosomes displayed faint or no CPAP immunoreactivity.…”

Section: Resultscontrasting

confidence: 57%

“…Mutations in centrosomal proteins cause developmental disorders such as primary microcephaly and Seckel syndrome (Thornton & Woods, 2009; Kalay et al , 2011; McIntyre et al , 2012; Lancaster et al , 2013; Alcantara & O'Driscoll, 2014; Bazzi & Anderson, 2014; Insolera et al , 2014; Martin et al , 2014). Microcephaly is a neurodevelopmental disorder leading to extreme reduction in brain size.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

CPAP promotes timely cilium disassembly to maintain neural progenitor pool

et al. 2016

View full text Add to dashboard Cite

A mutation in the centrosomal‐P4.1‐associated protein (CPAP) causes Seckel syndrome with microcephaly, which is suggested to arise from a decline in neural progenitor cells (NPCs) during development. However, mechanisms of NPCs maintenance remain unclear. Here, we report an unexpected role for the cilium in NPCs maintenance and identify CPAP as a negative regulator of ciliary length independent of its role in centrosome biogenesis. At the onset of cilium disassembly, CPAP provides a scaffold for the cilium disassembly complex (CDC), which includes Nde1, Aurora A, and OFD1, recruited to the ciliary base for timely cilium disassembly. In contrast, mutated CPAP fails to localize at the ciliary base associated with inefficient CDC recruitment, long cilia, retarded cilium disassembly, and delayed cell cycle re‐entry leading to premature differentiation of patient iPS‐derived NPCs. Aberrant CDC function also promotes premature differentiation of NPCs in Seckel iPS‐derived organoids. Thus, our results suggest a role for cilia in microcephaly and its involvement during neurogenesis and brain size control.

show abstract

Section: Resultscontrasting

confidence: 57%

Section: Introductionmentioning

confidence: 99%

CPAP promotes timely cilium disassembly to maintain neural progenitor pool

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Remarkably, CPAP and CEP152 are mutated in both MCPH and Seckel syndrome, suggesting that the two disorders might represent different ends of a disease continuum [26,100,102,144]. Indeed, recent reports uncovered mutations in the Seckel genes ATR and CtIP that cause primary microcephaly without PD, whereas short stature has been noted in some individuals with mutations in the MCPH gene, CDK5RAP2 [16,89,145].…”

Section: Perspectivesmentioning

confidence: 99%

“…If inactivation or clustering is efficient, cells can survive but at a cost; centrosome clustering causes not only mitotic delay, but also chromosomal instability [55,61]. Importantly, genome instability has been documented in CPAP-Seckel mouse and in Seckel patient-derived cells; CEP152-Seckel lymphocytes exhibit aneuploidy in addition to abnormal mitotic spindle morphologies [100,101].…”

Section: Centrosomes and Body Size (A) Primordial Dwarfism Syndromesmentioning

confidence: 99%

Small organelle, big responsibility: the role of centrosomes in development and disease

Chavali

Pütz

Gergely

2014

Phil. Trans. R. Soc. B

138

111

View full text Add to dashboard Cite

The centrosome, a key microtubule organizing centre, is composed of centrioles, embedded in a protein-rich matrix. Centrosomes control the internal spatial organization of somatic cells, and as such contribute to cell division, cell polarity and migration. Upon exiting the cell cycle, most cell types in the human body convert their centrioles into basal bodies, which drive the assembly of primary cilia, involved in sensing and signal transduction at the cell surface. Centrosomal genes are targeted by mutations in numerous human developmental disorders, ranging from diseases exclusively affecting brain development, through global growth failure syndromes to diverse pathologies associated with ciliary malfunction. Despite our much-improved understanding of centrosome function in cellular processes, we know remarkably little of its role in the organismal context, especially in mammals. In this review, we examine how centrosome dysfunction impacts on complex physiological processes and speculate on the challenges we face when applying knowledge generated from in vitro and in vivo model systems to human development.

show abstract

“…Genetic analysis has demonstrated that the biological roles of centrioles differ widely among organisms: Caenorhabditis elegans embryos without centrioles arrest at the two-cell stage, whereas zygotic removal of centrioles in Drosophila allows survival to adult stages (3)(4)(5). In humans, mutations in centriolar and centrosomal proteins are associated with microcephaly or microcephaly in the context of dwarfism (6)(7)(8)(9)(10). Abnormal numbers of centrioles are associated with cancer, although it is not clear whether abnormal centrosome number is a cause or an effect of tumorigenesis (1,(11)(12)(13).…”

mentioning

confidence: 99%

Acentriolar mitosis activates a p53-dependent apoptosis pathway in the mouse embryo

Bazzi

Anderson

2014

Proc. Natl. Acad. Sci. U.S.A.

174

201

View full text Add to dashboard Cite

Significance Centrioles form the core of centrosomes, which organize cilia and interphase and spindle microtubules in animal cells, but centrosome function has not been defined in mammals in vivo. We show that mouse embryos that lack centrioles and centrosomes survive to midgestation, when they lack primary cilia and cilia-dependent signaling. Despite the absence of centrosomes, bipolar spindle formation, chromosome segregation, cell-cycle profile, and DNA damage response are normal in the mutants. Unlike mutants that lack cilia, most cells in acentriolar embryos activate a p53-dependent apoptotic pathway. The data show that mammalian centrioles promote the efficient and rapid assembly of the mitotic spindle and that a short delay in prometaphase activates a checkpoint that leads to p53-dependent cell death in vivo.

show abstract

CEP152 is a genome maintenance protein disrupted in Seckel syndrome

Cited by 205 publications

References 15 publications

CPAP promotes timely cilium disassembly to maintain neural progenitor pool

CPAP promotes timely cilium disassembly to maintain neural progenitor pool

Small organelle, big responsibility: the role of centrosomes in development and disease

Acentriolar mitosis activates a p53-dependent apoptosis pathway in the mouse embryo

Contact Info

Product

Resources

About