Perinucleolar compartment

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The perinucleolar compartment (PNC) is a subnuclear body characterized by its location at the periphery of the nucleolus. [1] The PNC participates in the patterned compartmentalization inside the nucleus to organize the specialized functions. It is almost exclusively found in oncogenic cells and enriched with RNA binding proteins as well as RNA polymerase III transcripts.

Contents

History

The perinucleolar compartment was first discovered on the periphery of the nucleus in 1992 by Andrea Getti et al. while studying the hnRNPI/PTB (polypyrimidine tract binding) protein. [2] Getti found that in addition to the nucleoplasm, the hnRNPI was staining a “discrete unidentified structure” always opposite of the nucleoli. In 1995, A. Gregory Matera et al. first gave the structure its name “perinucleolar compartment” after finding several RNA polymerase III transcripts as well as hnRNPI at the nucleolar rim. [3] Sui Huang et al. has extensively researched the perinucleolar compartment and in 1997 were the first to study the PNC in a large number of human cancer cells. [4]

Small molecular probe that targets PNC in cancer cells. Small Molecule Probe Targeting Cancer (41658265005).jpg
Small molecular probe that targets PNC in cancer cells.

Structure

The PNC is a dynamic and irregular structure composed of multiple dense strands found primarily in transformed cancer cells. Electron microscopy on HeLa cells confirmed that the thick strands are 0.25 - 4 µm in length and 80 - 180 nm in diameter. [3] [4] These strands form a meshwork directly in contact with the nucleolus, and in some instances extend into the nucleolus.

RNA

The perinucleolar compartment relies on RNA binding proteins and RNA polymerase III transcripts to stabilize its structure. Therefore, the continuous production of these transcripts is pivotal. During permeabilization of cells, RNase, but not DNase, destroys the PNC establishing the importance of RNA to the structure. [1] Upon inhibition of RNA pol III transcripts, mature RNA pol III is not altered. Therefore, the PNC only relies on newly transcribed RNA pol III transcripts.

DNA

The perinucleolar compartment also relies on DNA integrity as well as a DNA locus for stability. DNA studies with DNA-intercalators, DNA-binding molecules, and DNA-damagers established that the PNC dissociates with certain DNA damage. [5] Additionally, DNA damage inhibitors do not prevent the disassembly of PNC, but they do prevent the reformation of the PNC proving the importance of DNA integrity.

The reliance on the DNA structure as well as the fact that daughter cells are exact replicates of the mother cells suggests the PNC is associated with a DNA locus, although, the exact locus is undetermined. In the S-phase of the cell cycle, the PNC nucleates at a DNA locus and replicates undisturbed with DNA. [5] This shows a direct correlation between PNC and DNA replication cycles, and further distinguishes the reliance of the perinucleolar compartment on DNA.

Function

Although the precise function has not been established, the perinucleolar compartment is concentrated with RNA binding proteins as well as newly transcribed RNA polymerase III transcripts indicating a probable role in RNA metabolism. Predominately found in transformed cancer cells, the prevalence is less than 5% in normal cell lines, but 15-100% in cancer cell lines. [6] The PNC is directly proportional to metastasis as well as linked to malignancy. [1] Thus, it is being further researched in its potential to be a biomarker for cancer.

Cell cycle

The perinucleolar compartment follows the mitotic pathway to form new daughter cells that are similar in size and shape to the mother cells. However, they can vary in size between different cancer cell lines. While remaining an individualized structure, the PNC remains in direct contact with the nucleoli during interphase and mimics the nucleoli during mitosis. In prophase, both gradually deconstruct until reassembly during late telophase in the new daughter cell. [4]

RNA metabolism

The perinucleolar compartment was first discovered due to characterizing the polypyrimidine tract-binding protein (PTB), which is an RNA binding protein involved with pre-mRNA splicing, stability, and regulating translation. [7] The PTB and other binding proteins are localized in the PNC to primarily process RNA polymerase II. In addition, many other small noncoding pol III RNA complexes which regulate pre-rRNA processing are localized in the PNC. [7] Hence, these PNC proteins may play a role in RNA metabolism and research is continually being conducted to scientifically prove this.

Clinical significance

Perinuclolar compartments form in blastomas, carcinomas, and sarcomas and exclusively represent malignant cells in solid tumor tissues. [1] [8] The occurrence of the PNC directly correlates with the growth and metastasis of cancer cells. For example, in a study on Hepatocellular carcinoma (HCC), there was a direct parallel between the increased occurrence of PNCs with an increase in metastasis as well as malignant cell lines. Likewise, the anti-metastasis was directly proportional to the PNC inhibition further demonstrating the potential for PNCs to be a biomarker across cancer. [9]

Related Research Articles

Nucleolus Largest structure in the nucleus of eukaryotic cells

The nucleolus is the largest structure in the nucleus of eukaryotic cells. It is best known as the site of ribosome biogenesis. Nucleoli also participate in the formation of signal recognition particles and play a role in the cell's response to stress. Nucleoli are made of proteins, DNA and RNA and form around specific chromosomal regions called nucleolar organizing regions. Malfunction of nucleoli can be the cause of several human conditions called "nucleolopathies" and the nucleolus is being investigated as a target for cancer chemotherapy.

Gene expression Conversion of a genes sequence into a mature gene product or products

Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, protein or non-coding RNA, and ultimately affect a phenotype, as the final effect. These products are often proteins, but in non-protein-coding genes such as transfer RNA (tRNA) and small nuclear RNA (snRNA), the product is a functional non-coding RNA. Gene expression is summarized in the central dogma of molecular biology first formulated by Francis Crick in 1958, further developed in his 1970 article, and expanded by the subsequent discoveries of reverse transcription and RNA replication.

Transcription (biology) Process of copying a segment of DNA into RNA

Transcription is the process of copying a segment of DNA into RNA. The segments of DNA transcribed into RNA molecules that can encode proteins are said to produce messenger RNA (mRNA). Other segments of DNA are copied into RNA molecules called non-coding RNAs (ncRNAs). Averaged over multiple cell types in a given tissue, the quantity of mRNA is more than 10 times the quantity of ncRNA. The general preponderance of mRNA in cells is valid even though less than 2% of the human genome can be transcribed into mRNA, while at least 80% of mammalian genomic DNA can be actively transcribed, with the majority of this 80% considered to be ncRNA.

Alternative splicing Process by which a gene can code for multiple proteins

Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be included within or excluded from the final, processed messenger RNA (mRNA) produced from that gene. This means the exons are joined in different combinations, leading to different (alternative) mRNA strands. Consequently, the proteins translated from alternatively spliced mRNAs will contain differences in their amino acid sequence and, often, in their biological functions.

In molecular biology and genetics, transcriptional regulation is the means by which a cell regulates the conversion of DNA to RNA (transcription), thereby orchestrating gene activity. A single gene can be regulated in a range of ways, from altering the number of copies of RNA that are transcribed, to the temporal control of when the gene is transcribed. This control allows the cell or organism to respond to a variety of intra- and extracellular signals and thus mount a response. Some examples of this include producing the mRNA that encode enzymes to adapt to a change in a food source, producing the gene products involved in cell cycle specific activities, and producing the gene products responsible for cellular differentiation in multicellular eukaryotes, as studied in evolutionary developmental biology.

Transcription preinitiation complex Complex of proteins necessary for gene transcription in eukaryotes and archaea

The preinitiation complex is a complex of approximately 100 proteins that is necessary for the transcription of protein-coding genes in eukaryotes and archaea. The preinitiation complex positions RNA polymerase II at gene transcription start sites, denatures the DNA, and positions the DNA in the RNA polymerase II active site for transcription.

SR protein

SR proteins are a conserved family of proteins involved in RNA splicing. SR proteins are named because they contain a protein domain with long repeats of serine and arginine amino acid residues, whose standard abbreviations are "S" and "R" respectively. SR proteins are ~200-600 amino acids in length and composed of two domains, the RNA recognition motif (RRM) region and the RS domain. SR proteins are more commonly found in the nucleus than the cytoplasm, but several SR proteins are known to shuttle between the nucleus and the cytoplasm.

Primary transcript RNA produced by transcription

A primary transcript is the single-stranded ribonucleic acid (RNA) product synthesized by transcription of DNA, and processed to yield various mature RNA products such as mRNAs, tRNAs, and rRNAs. The primary transcripts designated to be mRNAs are modified in preparation for translation. For example, a precursor mRNA (pre-mRNA) is a type of primary transcript that becomes a messenger RNA (mRNA) after processing.

RNA polymerase 1 is, in higher eukaryotes, the polymerase that only transcribes ribosomal RNA, a type of RNA that accounts for over 50% of the total RNA synthesized in a cell.

RNA polymerase II Protein complex that transcribes DNA

RNA polymerase II is a multiprotein complex that transcribes DNA into precursors of messenger RNA (mRNA) and most small nuclear RNA (snRNA) and microRNA. It is one of the three RNAP enzymes found in the nucleus of eukaryotic cells. A 550 kDa complex of 12 subunits, RNAP II is the most studied type of RNA polymerase. A wide range of transcription factors are required for it to bind to upstream gene promoters and begin transcription.

In eukaryote cells, RNA polymerase III is a protein that transcribes DNA to synthesize ribosomal 5S rRNA, tRNA and other small RNAs.

Heterogeneous nuclear ribonucleoproteins (hnRNPs) are complexes of RNA and protein present in the cell nucleus during gene transcription and subsequent post-transcriptional modification of the newly synthesized RNA (pre-mRNA). The presence of the proteins bound to a pre-mRNA molecule serves as a signal that the pre-mRNA is not yet fully processed and therefore not ready for export to the cytoplasm. Since most mature RNA is exported from the nucleus relatively quickly, most RNA-binding protein in the nucleus exist as heterogeneous ribonucleoprotein particles. After splicing has occurred, the proteins remain bound to spliced introns and target them for degradation.

Paraspeckle Cell compartment found in the nucleuss interchromatin space

In cell biology, a paraspeckle is an irregularly shaped compartment of the cell, approximately 0.2-1 μm in size, found in the nucleus' interchromatin space. First documented in HeLa cells, where there are generally 10-30 per nucleus, Paraspeckles are now known to also exist in all human primary cells, transformed cell lines and tissue sections. Their name is derived from their distribution in the nucleus; the "para" is short for parallel and the "speckle" refers to the splicing speckles to which they are always in close proximity. Their function is still not fully understood, but they are thought to regulate gene expression by sequestrating proteins or mRNAs with inverted repeats in their 3′ UTRs.

Eukaryotic transcription Transcription is heterocatalytic function of DNA

Eukaryotic transcription is the elaborate process that eukaryotic cells use to copy genetic information stored in DNA into units of transportable complementary RNA replica. Gene transcription occurs in both eukaryotic and prokaryotic cells. Unlike prokaryotic RNA polymerase that initiates the transcription of all different types of RNA, RNA polymerase in eukaryotes comes in three variations, each translating a different type of gene. A eukaryotic cell has a nucleus that separates the processes of transcription and translation. Eukaryotic transcription occurs within the nucleus where DNA is packaged into nucleosomes and higher order chromatin structures. The complexity of the eukaryotic genome necessitates a great variety and complexity of gene expression control.

HNRNPK Protein-coding gene in the species Homo sapiens

Heterogeneous nuclear ribonucleoprotein K is a protein that in humans is encoded by the HNRNPK gene. It is found in the cell nucleus that binds to pre-messenger RNA (mRNA) as a component of heterogeneous ribonucleoprotein particles. The simian homolog is known as protein H16. Both proteins bind to single-stranded DNA as well as to RNA and can stimulate the activity of RNA polymerase II, the protein responsible for most gene transcription. The relative affinities of the proteins for DNA and RNA vary with solution conditions and are inversely correlated, so that conditions promoting strong DNA binding result in weak RNA binding.

HNRPU Protein-coding gene in the species Homo sapiens

Heterogeneous nuclear ribonucleoprotein U is a protein that in humans is encoded by the HNRNPU gene.

HNRNPC

Heterogeneous nuclear ribonucleoproteins C1/C2 is a protein that in humans is encoded by the HNRNPC gene.

SFPQ Non-coding RNA in the species Homo sapiens

Splicing factor, proline- and glutamine-rich is a protein that in humans is encoded by the SFPQ gene.

HNRNPL Protein-coding gene in the species Homo sapiens

Heterogeneous nuclear ribonucleoprotein L is a protein that in humans is encoded by the HNRNPL gene.

PTBP1 Protein-coding gene in the species Homo sapiens

Polypyrimidine tract-binding protein 1 is a protein that in humans is encoded by the PTBP1 gene.

References

  1. 1 2 3 4 Pollock C, Huang S (February 2010). "The perinucleolar compartment". Cold Spring Harbor Perspectives in Biology. 2 (2): a000679. doi:10.1101/cshperspect.a000679. PMC   2828281 . PMID   20182614.
  2. ↑ Ghetti A, Piñol-Roma S, Michael WM, Morandi C, Dreyfuss G (July 1992). "hnRNP I, the polypyrimidine tract-binding protein: distinct nuclear localization and association with hnRNAs". Nucleic Acids Research. 20 (14): 3671–3678. doi:10.1093/nar/20.14.3671. PMID   1641332.
  3. 1 2 Matera AG, Frey MR, Margelot K, Wolin SL (June 1995). "A perinucleolar compartment contains several RNA polymerase III transcripts as well as the polypyrimidine tract-binding protein, hnRNP I". The Journal of Cell Biology. 129 (5): 1181–1193. doi:10.1083/jcb.129.5.1181. PMC   2120477 . PMID   7539809.
  4. 1 2 3 Huang S, Deerinck TJ, Ellisman MH, Spector DL (June 1997). "The dynamic organization of the perinucleolar compartment in the cell nucleus". The Journal of Cell Biology. 137 (5): 965–974. doi:10.1083/jcb.137.5.965. PMC   2136227 . PMID   9166399.
  5. 1 2 Norton JT, Wang C, Gjidoda A, Henry RW, Huang S (February 2009). "The perinucleolar compartment is directly associated with DNA". The Journal of Biological Chemistry. 284 (7): 4090–4101. doi:10.1074/jbc.M807255200. PMC   2640956 . PMID   19015260.
  6. ↑ Norton JT, Pollock CB, Wang C, Schink JC, Kim JJ, Huang S (August 2008). "Perinucleolar compartment prevalence is a phenotypic pancancer marker of malignancy". Cancer. 113 (4): 861–869. doi:10.1002/cncr.23632. PMC   4780316 . PMID   18543322.
  7. 1 2 Norton JT, Huang S (2013). Wu JY (ed.). "The perinucleolar compartment: RNA metabolism and cancer". Cancer Treatment and Research. Berlin, Heidelberg: Springer. 158: 139–152. doi:10.1007/978-3-642-31659-3_6. ISBN   978-3-642-31659-3. PMC   4374481 . PMID   24222357.
  8. ↑ Wen Y, Wang C, Huang S (August 2013). "The perinucleolar compartment associates with malignancy". Frontiers in Biology. 8 (4): 369–376. doi:10.1007/s11515-013-1265-z. PMC   3862354 . PMID   24348523.
  9. ↑ Liu F, Lou G, Zhang T, Chen S, Xu J, Xu L, et al. (2019-06-15). "Anti-metastasis traditional Chinese medicine monomer screening system based on perinucleolar compartment analysis in hepatocellular carcinoma cells". American Journal of Translational Research. 11 (6): 3555–3566. PMC   6614616 . PMID   31312366.
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