# CENPJ

## Overview
CENPJ is a gene that encodes the protein centromere protein J, also known as CPAP, which plays a critical role in centriole biogenesis and spindle positioning within human cells. CPAP is a large coiled-coil protein that is integral to the centrosome, a key cellular structure involved in cell division. The protein is characterized by multiple domains that facilitate its interactions with other proteins, such as STIL and hSAS6, which are essential for procentriole formation and centriole duplication (Kitagawa2011Spindle; Tang2011The). CENPJ is particularly significant in neurodevelopment, as it is crucial for maintaining a large pool of neural progenitors, thereby influencing brain size and development (Shi2013HumanSpecific). Mutations in CENPJ are associated with developmental disorders such as primary microcephaly and Seckel syndrome, underscoring its importance in proper cellular and developmental processes (McIntyre2012Disruption).

## Structure
The CENPJ gene encodes the CPAP protein, which is essential for centriole formation in human cells. CPAP is a large protein composed of 1338 amino acids and features several structural domains that contribute to its function. It contains five coiled-coil regions, which facilitate protein-protein interactions and are crucial for its homodimerization, particularly the CC5 region near the G-box domain (Kitagawa2011Spindle; Jaiswal2023Separation). The protein also includes a C-terminal TCP domain, which is important for centriole cartwheel assembly by interacting with the cartwheel protein STIL (Kitagawa2011Spindle; Jaiswal2023Separation).

The PN2-3 domain of CPAP is involved in microtubule destabilization, while the A5N domain stabilizes microtubules, highlighting its role in regulating centriole length (Jaiswal2023Separation). The G-box/TCP domain is glycine-rich and plays a critical role in centriole assembly and length regulation, with mutations in this domain affecting centriole number and length (Jaiswal2023Separation).

CPAP's interaction with STIL is essential for its recruitment to the centriole, although an alternative CEP152-dependent pathway can also facilitate its localization (Jaiswal2023Separation). The protein's structure and interactions are vital for its function in centriole formation and spindle positioning, which are crucial for proper brain development (Kitagawa2011Spindle).

## Function
CENPJ, also known as centromere protein J, encodes the protein CPAP, which is essential for centriole formation and spindle positioning in human cells. CPAP is a large coiled-coil protein enriched at the centrosome, a structure that includes two centrioles and surrounding pericentriolar material (PCM). Proper centriole formation is crucial for accurate spindle positioning during cell division, which is vital for maintaining genomic stability and proper cell cycle progression (Kitagawa2011Spindle).

CPAP is involved in several molecular processes, including centriole elongation and microtubule organization. It contains multiple domains, such as the PN2-3 domain, which binds tubulin dimers and is important for centriole elongation (Kitagawa2011Spindle). CPAP also interacts with other proteins like STIL and hSAS6, forming a complex essential for procentriole formation and centriole duplication (Tang2011The).

In the context of brain development, CENPJ is crucial for maintaining a large pool of neural progenitors, which is associated with larger brain size. Its expression is particularly high during fetal brain development, suggesting a key role in neurogenesis (Shi2013HumanSpecific).

## Clinical Significance
Mutations in the CENPJ gene are linked to several developmental disorders, most notably primary microcephaly and Seckel syndrome. Primary microcephaly is characterized by a significantly reduced brain size, while Seckel syndrome involves severe reductions in both brain and body size, mental retardation, and skeletal abnormalities (McIntyre2012Disruption). Specific mutations in CENPJ, such as those affecting exons 2, 11, and 16, are associated with microcephaly, whereas a homozygous splice acceptor mutation in intron 11 is linked to Seckel syndrome (McIntyre2012Disruption).

In mouse models, disruption of the CENPJ gene results in phenotypes that mimic Seckel syndrome, including intrauterine and postnatal dwarfism, microcephaly, and genomic instability. These mice exhibit irregular centriole numbers, mitotic spindle abnormalities, and increased apoptosis, particularly in the embryonic brain (McIntyre2012Disruption). The genomic instability observed in these models is not due to defects in ATR or ATM-dependent DNA damage signaling, suggesting alternative mechanisms are involved (McIntyre2012Disruption).

Alterations in CENPJ expression can lead to neurodevelopmental issues and cognitive impairments, consistent with the symptoms observed in Seckel syndrome (McIntyre2012Disruption). The gene's disruption also results in skeletal abnormalities, such as smaller skulls and irregular ribcages, which are characteristic of Seckel syndrome (McIntyre2012Disruption).

## Interactions
CENPJ, also known as CPAP, is a protein that plays a crucial role in centriole duplication and interacts with several other proteins to perform its functions. It directly interacts with the human microcephaly protein STIL, forming a complex with hSAS6, which is essential for procentriole formation. The interaction domain of STIL with CPAP is located in the central region of STIL, and mutations in CPAP can reduce its binding affinity to STIL, potentially leading to primary microcephaly (Tang2011The).

CENPJ also interacts with centrosomal proteins such as CEP152, which provides an alternative pathway for its recruitment to centrioles, independent of STIL. This interaction is significant in regulating centriole number and length, particularly in the context of microcephaly mutations (Jaiswal2023Separation).

In the context of spermatogenesis, CENPJ is found to interact with the serine/threonine kinase HASPIN, which is involved in cell division processes. This interaction is confirmed through co-transfection experiments, indicating a potential role in spermatid development (Maeda2022Analysis).

These interactions highlight the multifaceted role of CENPJ in cellular processes, particularly in centriole biogenesis and cell division.


## References


[1. (Tang2011The) Chieh-Ju C Tang, Shin-Yi Lin, Wen-Bin Hsu, Yi-Nan Lin, Chien-Ting Wu, Yu-Chih Lin, Ching-Wen Chang, Kuo-Sheng Wu, and Tang K Tang. The human microcephaly protein stil interacts with cpap and is required for procentriole formation: stil is required for procentriole formation. The EMBO Journal, 30(23):4790–4804, October 2011. URL: http://dx.doi.org/10.1038/emboj.2011.378, doi:10.1038/emboj.2011.378. This article has 213 citations.](https://doi.org/10.1038/emboj.2011.378)

[2. (Maeda2022Analysis) Naoko Maeda, Junji Tsuchida, Yoshitake Nishimune, and Hiromitsu Tanaka. Analysis of ser/thr kinase haspin-interacting proteins in the spermatids. International Journal of Molecular Sciences, 23(16):9060, August 2022. URL: http://dx.doi.org/10.3390/ijms23169060, doi:10.3390/ijms23169060. This article has 1 citations and is from a peer-reviewed journal.](https://doi.org/10.3390/ijms23169060)

3. (Jaiswal2023Separation) Separation of function mutations in microcephaly protein CPAP/CENPJ, reveal its role in regulating centriole number and length. This article has 0 citations.

[4. (Shi2013HumanSpecific) Lei Shi, Qiang Lin, and Bing Su. Human-specific hypomethylation of cenpj, a key brain size regulator. Molecular Biology and Evolution, 31(3):594–604, November 2013. URL: http://dx.doi.org/10.1093/molbev/mst231, doi:10.1093/molbev/mst231. This article has 19 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1093/molbev/mst231)

[5. (Kitagawa2011Spindle) Daiju Kitagawa, Gregor Kohlmaier, Debora Keller, Petr Strnad, Fernando R. Balestra, Isabelle Flückiger, and Pierre Gönczy. Spindle positioning in human cells relies on proper centriole formation and on the microcephaly proteins cpap and stil. Journal of Cell Science, 124(22):3884–3893, November 2011. URL: http://dx.doi.org/10.1242/jcs.089888, doi:10.1242/jcs.089888. This article has 91 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1242/jcs.089888)

[6. (McIntyre2012Disruption) Rebecca E. McIntyre, Pavithra Lakshminarasimhan Chavali, Ozama Ismail, Damian M. Carragher, Gabriela Sanchez-Andrade, Josep V. Forment, Beiyuan Fu, Martin Del Castillo Velasco-Herrera, Andrew Edwards, Louise van der Weyden, Fengtang Yang, Ramiro Ramirez-Solis, Jeanne Estabel, Ferdia A. Gallagher, Darren W. Logan, Mark J. Arends, Stephen H. Tsang, Vinit B. Mahajan, Cheryl L. Scudamore, Jacqueline K. White, Stephen P. Jackson, Fanni Gergely, and David J. Adams. Disruption of mouse cenpj, a regulator of centriole biogenesis, phenocopies seckel syndrome. PLoS Genetics, 8(11):e1003022, November 2012. URL: http://dx.doi.org/10.1371/journal.pgen.1003022, doi:10.1371/journal.pgen.1003022. This article has 82 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1371/journal.pgen.1003022)