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- Table of Contents
Facts about Histone H3-like centromeric protein A.
The existence of CENPA subtly modifies the nucleosome structure and how DNA is wrapped around the nucleosome and gives rise to protruding DNA ends that are less well-ordered and rigid in comparison to nucleosomes containing histone H3 (PubMed:27499292, PubMed:26878239). May serve as an epigenetic mark that propagates centromere identity through replication and cell division (PubMed:15475964, PubMed:15282608, PubMed:26878239, PubMed:20739937, PubMed:21478274).
Human | |
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Gene Name: | CENPA |
Uniprot: | P49450 |
Entrez: | 1058 |
Belongs to: |
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histone H3 family |
Centromere autoantigen A; centromere protein A (17kD); centromere protein ACENP-Acentromere protein A, 17kDa; histone H3-like centromeric protein A
Mass (kDA):
15.991 kDA
Human | |
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Location: | 2p23.3 |
Sequence: | 2; NC_000002.12 (26786015..26794589) |
Nucleus. Chromosome, centromere, kinetochore. Chromosome, centromere. Localizes exclusively in the kinetochore domain of centromeres. Occupies a compact domain at the inner kinetochore plate stretching across 2 thirds of the length of the constriction but encompassing only one third of the constriction width and height (PubMed:19114591). Phosphorylation at Ser-68 during early mitosis abolishes association with chromatin and centromeres and results in dispersed nuclear location (PubMed:25556658).
There are many different uses for the CENPA marker. This single-exon gene is found on centromeres and is a candidate for epigenetic marking of the kinetochore. In this article, I will explain the most common uses for this marker and what it means for you. We'll also look at some of its applications in cancer and autoimmune disease research.
The genome of the mouse has a single CENPA gene (also abbreviated CB455530). This protein displays an exceptionally high degree of conservation among all regions, with the exception of the tail and Loop 1 region. These regions have undergone selective evolution in rodents and primates. Adaptive evolution also influenced the CENPC motif, which was previously found to be mutated in chimpanzees.
CENP-A is an insertion of 25 amino acids in the mouse genome. It is important for faithful chromosome segregation and genome integrity maintenance. The CENP-A protein defines the position of the centromere and provides the foundation for building kinetochores. Several types of cancer display overexpression of this gene, with high levels of CENP-A mislocalizing outside of the centromere. In recent years, however, scientists have begun to understand how overexpression of CENP-A affects the development of cancer.
CENP-A expression levels are linked with poor prognosis and cancer progression. However, this level of CENP-A is not sufficient to induce EMT in p53-deficient cells. Moreover, this gene's function in cells in transition may depend on the type of cell being studied. This gene can be a potential biomarker for the treatment of cancer. However, further research is needed to better understand how CENP-A regulates gene expression in cancer cells.
CENP-A contains multiple genes and is an important biomarker for hepatocellular carcinoma. Overexpression of CENP-A can result in ectopic incorporation of the protein into chromosome arms. This leads to aneuploidy and chromosomal instability. The mislocalization of the gene also affects chromatin organization. Therefore, it is important to understand the mechanism by which CENP-A overexpression causes cancer.
CENP-A and HJURP co-regulate in several cancers, where CENP-A is upregulated simultaneously with HJURP. Studies conducted in 2009 and 2021 revealed significant correlation between the two genes' mRNA levels. It is believed that these two proteins act together to stabilize HJURP. The posttranslational modifications of CENP-A and HJURP affect their mutual stabilization.
The CenpC motif is conserved throughout the protein's length in both plant and animal species. The amino and carboxyl termini of the encoded proteins are very similar, suggesting that they might serve the same functions. In addition to the CENPC motif, the sequence of the Arabidopsis thaliana gene is very similar, with the CENPC motif encoded in exon 10.
The sequence of the maize and primate CenH3 genes is different. While the mammalian CENP-C gene is 93% identical, it is significantly more complex in S. paradoxus. Adaptive evolution in the CenH3 gene appears to be episodic and erratic, with positive selection in certain regions but not in others. The results from the maize CenpcA lineage suggest that positive selection has a significant impact in the evolution of the gene.
CENP-A is a constituent nucleosome found in the human regional centromere. It is flanked by outer regions of heterochromatin. Its a-satellite repeats are organized in a higher-order repeat pattern but are not essential for centromere location. Instead, they may participate in the stability and formation of pericentromeric heterochromatin, the outer boundary of the centromere. These a-satellite repeats contain the 17-bp CENP-B box motif.
CENP-A also plays a role in packaging centromeric chromatin during interphase. These studies suggest that CENP-A is an epigenetic marker for centromere formation. However, further studies are needed to clarify the role of this protein in centromere formation. In addition, CENP-A has a unique post-translational modification that is implicated in numerous centromere processes, including incorporation of chromosomal regions for kinetochore assembly.
CENP-A is a component of the core centromere. It interacts with centromeric DNA sequences and is associated with interphase arrest in HeLa cells. In contrast, midinterphase injection of CENP-A antibody did not disrupt mitosis, but caused a mitotic lag. CENP-A and CSE4p, two components of the core centromere, are a major target for mutation.
CENP-A contributes to the integrity of centromeres in human cells. Excessive levels of Cenp-A may lead to genome instability, chromosome missegregation and tumorigenesis. This is why Cenp-A is an essential molecule that contributes to the health of the centromeres. However, the precise role of Cenp-A in human cancer is unknown.
CENP-A is an epigenetically-specified centromere protein. As such, CENP-A deposition is regulated by cell cycle machinery. The activation of the anaphase promoting complex and degradation of CYCLIN A are important for deposition of CID. Other components of the cell cycle control centromere assembly, including the CYCLIN B/Cdk1 complex, inhibit CENP-A binding to HJURP and prevent CENP-A from loading at centromeres.
CENP-A is a component of the centromeric chromatin during mitosis and must be maintained at the centromere during each cell division to ensure faithful segregation of chromosomes. CENP-A and CENP-B contain the CENP-B box motif present on mouse and human a-satellite DNA. This complex is crucial for chromosome faithfulness.
CENP-A nucleosomes are assembled with the CCNC in yeast and Xenopus. CENP-C nucleosomes can be assembled on the 601 sequence, where CENP-C and CENP-N are bound. CENP-A nucleosomes are assembled on a-satellite DNA and assemble robustly.
The protein CENPA is a candidate for epigenetically marking kinetochore proteins. During mitosis and centromeric replication, the CENP-A nucleosome is modified. This cyclical modification promotes binding of key kinetochore proteins. These findings suggest that modification of histone variants may affect the function of these proteins.
CENP-A has been implicated in the formation of functional HA-CENP-A HACs in fibrosarcoma cells. It also promotes the recruitment of kinetochores and promotes chromosome segregation fidelity. The B-box i-motifs are also implicated in the nucleosome environment and improve kinetochore activity.
In budding yeast, kinetochore activity requires low levels of CEN transcription. RNAPII drives CEN transcription, and the PGAL1 promoter may be placed adjacent to the chromosome's CEN3 gene. However, deactivation of these genes does not prevent the formation of kinetochores but causes loss of chromosomes. The inducible promoters can rescue the mutant phenotype and restore the chromosomes. Moreover, CEN transcription is crucial for kinetochore activity.
To further understand how these modifications may influence the mechanism of epigenetic marking of kinetochrome, researchers performed all-atom MD simulations on the CENP-A nucleosome. In this way, CENP-A and CENP-C are altered to inhibit the formation of DNA bubbles, allowing access to nucleosomal DNA.
The interaction of CENP-A and CENP-C with CEN RNA was first discovered at the human neocentromere. Both proteins interact with HJURP, and interaction with HJURP has been shown in alpha-satellite transcript pull-down experiments. In addition, in-silico predictions of potential RNA-binding sites revealed that 286 out of 748 HJURP residues and 79 CENP-A residues have RNA-binding activity. The remaining residues may be bound by CENP-C or buried within the nucleosome.
The CENP-A nucleosomes are found at the beginning and the end of the nucleosome in two different models. CENP-A is also found at the surface of the chromatin. In these models, CENPA plays an important role in kinetochore formation. These two proteins may act in tandem with CEN-A and CEN-B in chromatin folding.
Its role in kinetochore formation is unknown, but it is an epigenetic marker of this complex. Nonetheless, its effects on CENPA activity have been shown to be significant. The repressive marks that CEN-C loses cause satellite overexpression and disrupted kinetochore formation. This is a promising avenue for further research.
PMID: 7962047 by Sullivan K.F., et al. Human CENP-A contains a histone H3 related histone fold domain that is required for targeting to the centromere.
PMID: 9024683 by Shelby R.D., et al. Assembly of CENP-A into centromeric chromatin requires a cooperative array of nucleosomal DNA contact sites.