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.

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.

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]

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. PMC 334017. 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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