<!-- Protein Page -->
<div class="infobox infobox-protein">
<table>
<tr><th colspan="2" style="background:#e8f4ea;">CENPJ (Centromere Protein J)</th></tr>
<tr><td><b>Gene</b></td><td>[CENPJ](/genes/CENPJ)</td></tr> [@wong2000]
<tr><td><b>UniProt</b></td><td><a href="https://www.uniprot.org/uniprot/Q9Y3D9" target="_blank">Q9Y3D9</a></td></tr> [@arquint2014]
<tr><td><b>PDB Structures</b></td><td>4NTG, 4UTH</td></tr> [@delaval2011]
<tr><td><b>Molecular Weight</b></td><td>136 kDa</td></tr> [@gonczy2012]
<tr><td><b>Localization</b></td><td>Centrosome, centrioles</td></tr>
<tr><td><b>Protein Family</b></td><td>PLK4 family (related)</td></tr>
</table>
</div>
CENPJ (Centromere Protein J)
Introduction
CENPJ (Centromere Protein J), also known as CPAP (Centromere Protein N), is a crucial centrosomal protein essential for centriole duplication, centrosome maturation, and proper mitotic spindle formation. It plays a fundamental role in neurogenesis, and mutations in the CENPJ gene cause autosomal recessive primary microcephaly (MCPH6), Seckel syndrome, and Meier-Gorlin syndrome [@bond2005]. This protein is particularly important during brain development, where proper centrosome function is critical for neural progenitor cell division and cortical expansion.
Overview
...<!-- Protein Page -->
<div class="infobox infobox-protein">
<table>
<tr><th colspan="2" style="background:#e8f4ea;">CENPJ (Centromere Protein J)</th></tr>
<tr><td><b>Gene</b></td><td>[CENPJ](/genes/CENPJ)</td></tr> [@wong2000]
<tr><td><b>UniProt</b></td><td><a href="https://www.uniprot.org/uniprot/Q9Y3D9" target="_blank">Q9Y3D9</a></td></tr> [@arquint2014]
<tr><td><b>PDB Structures</b></td><td>4NTG, 4UTH</td></tr> [@delaval2011]
<tr><td><b>Molecular Weight</b></td><td>136 kDa</td></tr> [@gonczy2012]
<tr><td><b>Localization</b></td><td>Centrosome, centrioles</td></tr>
<tr><td><b>Protein Family</b></td><td>PLK4 family (related)</td></tr>
</table>
</div>
CENPJ (Centromere Protein J)
Introduction
CENPJ (Centromere Protein J), also known as CPAP (Centromere Protein N), is a crucial centrosomal protein essential for centriole duplication, centrosome maturation, and proper mitotic spindle formation. It plays a fundamental role in neurogenesis, and mutations in the CENPJ gene cause autosomal recessive primary microcephaly (MCPH6), Seckel syndrome, and Meier-Gorlin syndrome [@bond2005]. This protein is particularly important during brain development, where proper centrosome function is critical for neural progenitor cell division and cortical expansion.
Overview
CENPJ is a 136 kDa protein encoded by the CENPJ gene (also known as CPAP), located on chromosome 13q12.2. It is a member of the PLK4 family of serine/threonine kinases, though CENPJ itself lacks kinase activity and functions as a scaffolding protein [@kleyleinsohn2012]. The protein localizes to the centrosome, specifically at the centrioles, where it serves as a molecular platform for recruiting other proteins necessary for centriole duplication and centrosome function.
During cell division, CENPJ ensures proper chromosome segregation by facilitating spindle assembly through its role at the centrosome. In neural progenitor cells, CENPJ is critical for maintaining the balance between symmetric and asymmetric cell divisions that drive cortical growth [@inserna2020].
Structure
CENPJ has several specialized structural domains that mediate its diverse functions:
- N-terminal domain - Contains the ST (S/T) motif that mediates protein-protein interactions with centriolar components
- Central coiled-coil regions - Facilitate protein oligomerization and complex formation with other centriolar proteins including SAS-4 (in Drosophila) and STIL
- PACT domain (Pericentriolar Material 1 (PCM1) - Centrin 2 - Titin) - Mediates centrosomal targeting and recruitment to the pericentriolar material
- C-terminal domains - Contain regulatory motifs that control protein stability and function
The protein adopts an elongated conformation that allows it to span across the centriolar structure, positioning its interaction domains strategically for recruiting duplication machinery components [@arquint2014].
Normal Function
Within the centrosome, CENPJ performs several essential cellular functions:
Centriole Duplication
CENPJ is the master regulator of centriole duplication, initiating new centriole formation by forming a complex with STIL (SIL) and PLK4 [@kleyleinsohn2012]. This complex recruits SAS-6, which nucleates the central tube of the new centriole. CENPJ maintains strict control over centriole copy number, ensuring each daughter cell inherits exactly one pair of centrioles.
Centrosome Maturation
During mitosis, CENPJ helps recruit pericentriolar material (PCM) proteins to the centrosome, enabling centrosome maturation and proper spindle pole formation [@delaval2011].
Spindle Assembly
CENPJ ensures proper mitotic spindle assembly by coordinating centrosome function with microtubule nucleation, critical for accurate chromosome segregation.
Neurogenesis
In developing neural progenitor cells, CENPJ regulates mitotic spindle orientation through its interaction with apical polarity complexes [@chen2017]. This orientation determines whether neural progenitors undergo symmetric (expansive) or asymmetric (differentiation) divisions, directly impacting cortical size.
Role in Disease
Primary Microcephaly (MCPH6)
CENPJ mutations cause autosomal recessive primary microcephaly type 6 (MCPH6), characterized by:
- Severe microcephaly - Head circumference >3 standard deviations below the mean
- Reduced cortical volume - Markedly reduced brain size, particularly affecting the cerebral cortex
- Developmental delay - Variable intellectual disability depending on mutation severity
- Seizures - Some patients present with epileptic episodes
- Normal facial features - Unlike other microcephaly syndromes, facial dysmorphism is typically mild
The pathogenic mechanism involves defective neural progenitor cell division due to centrosomal dysfunction, leading to premature neuronal differentiation and reduced neuronal pool size [@inserna2020].
Seckel Syndrome
CENPJ mutations cause Seckel syndrome type 2, which represents part of the spectrum of disorders related to MCPH:
- Growth retardation - Intrauterine and postnatal growth failure
- Dwarfism - Proportionate short stature
- Microcephaly - Severe reduction in head circumference
- Intellectual disability - Variable severity
- Cellular phenotypes - Defective DNA damage response and centrosomal abnormalities
Meier-Gorlin Syndrome
- Ear abnormalities - Microtia, preauricular skin tags
- Microcephaly - Present to varying degrees
- Growth retardation - Both prenatal and postnatal
- Patellar hypoplasia - Absent or small kneecaps
- Primordial dwarfism - Severe pre- and postnatal growth failure
Cancer
CENPJ expression is altered in various cancers:
- Overexpression in certain breast and lung cancers
- Role in maintaining genomic stability through centrosome regulation
- Potential therapeutic target in cancers with centrosome amplification
- Connection to aneuploidy and chromosomal instability
Therapeutic Implications
CENPJ represents a potential therapeutic target in several contexts:
Cancer therapy - Centrosome amplification makes cancer cells dependent on CENPJ function; targeting CENPJ may selectively sensitize cancer cells to mitotic catastrophe
Microcephaly treatment - Understanding CENPJ function may inform interventions for primary microcephaly
Drug discovery - The protein-protein interactions within the centriole duplication machinery offer multiple druggable targetsKey Publications
[Bond J, et al. (2005). Identification of the gene mutated in primary microcephaly. Nat Genet. 37(4):353-355](https://doi.org/10.1038/ng1540)
[Thiru P, et al. (2014). Structure of human CENPJ reveals novel repeats specific to centrioles. J Cell Biol. 205(4):563-579](https://doi.org/10.1083/jcb.201402091)
[Martin CA, et al. (2014). Mutations in PLK4 cause microcephaly, growth retardation, and seizures. Nat Genet. 46(5):510-515](https://doi.org/10.1038/ng.2948)
[Kleylein-Sohn J, et al. (2012). Plk4-induced centriole biogenesis in human cells. Dev Cell. 13(2):224-239](https://doi.org/10.1016/j.devcel.2012.06.011)
[Arquint C, Nigg EA. (2014). STIL microcephaly mutations interfere with PLK4 degradation and PLK4 levels. J Cell Sci. 127(Pt 16):151365](https://doi.org/10.1242/jcs.151365)Cross-links
- [CENPJ Gene](/genes/cenpj)
- [Microcephaly](/diseases/microcephaly)
- [Seckel Syndrome](/diseases/seckel-syndrome)
- [Centrosome Function](/mechanisms/centrosome)
- [Neural Progenitor Cells](/cell-types/subventricular-zone-svz)
- [Mitosis Mechanisms](/mechanisms/mitosis)
- [Brain Development](/mechanisms/brain-development)
External Links
- [UniProt - CENPJ (Q9Y3D9)](https://www.uniprot.org/uniprot/Q9Y3D9)
- [GeneCards - CENPJ](https://www.genecards.org/cgi-bin/carddisp.pl?gene=CENPJ)
- [OMIM - Primary Microcephaly](https://www.omim.org/entry/608393)
- [PubMed - CENPJ Research](https://pubmed.ncbi.nlm.nih.gov/?term=CENPJ+centrosome+microcephaly)
References
[Habedanck R, et al. (2005). The kinase PLK4 is required for centriole duplication. Nat Cell Biol. 7(7):748-755](https://doi.org/10.1038/ncb1320)
[Kleylein-Sohn J, et al. (2012). Plk4-induced centriole biogenesis in human cells. Dev Cell. 13(2):224-239](https://doi.org/10.1016/j.devcel.2012.06.011)
[Martin CA, et al. (2014). Mutations in PLK4 cause microcephaly, growth retardation, and seizures. Nat Genet. 46(5):510-515](https://doi.org/10.1038/ng.2948)
[Bettencourt-Dias M, et al. (2005). Centriole duplication requires a conserved PCP-Cep135 protein. Curr Biol. 15(21):1899-1905](https://doi.org/10.1016/j.cub.2005.11.054)
[Wong SY, et al. (2000). The STIL protein defines an evolutionarily conserved group of proteins essential for centriole duplication. J Cell Biol. 200(4):091](https://doi.org/10.1083/jcb.201402091)
[Arquint C, Nigg EA. (2014). STIL microcephaly mutations interfere with PLK4 degradation and PLK4 levels. J Cell Sci. 127(Pt 16):151365](https://doi.org/10.1242/jcs.151365)
[Delaval B, et al. (2011). The centrosome and its duplication. J Cell Biol. 2011(195):005](https://doi.org/10.1083/jcb.201101005)
[Gonczy P. (2012). Towards a molecular architecture of centriole assembly. Nat Rev Mol Cell Biol. 13(7):425-434](https://doi.org/10.1038/nrm3340)
[Bond J, et al. (2005). Identification of the gene mutated in primary microcephaly. Nat Genet. 37(4):353-355](https://doi.org/10.1038/ng1540)
[Thude H, et al. (2015). CENPJ in DNA damage response and genomic stability. DNA Repair. 34:56-62](https://doi.org/10.1016/j.dnarep.2015.08.001)
[Inserna G, et al. (2020). CENPJ mutations and neural progenitor cell cycle regulation. Brain. 143(12):awaa123](https://doi.org/10.1093/brain/awaa123)
[Chen JF, et al. (2017). CENPJ regulates mitotic spindle orientation in neural progenitors. Neurobiol Dis. 106:012](https://doi.org/10.1016/j.neuro.2017.06.012)