The perinucleolar compartment (PNC) is a subnuclear body characterized by its location at the periphery of the

nucleolus The nucleolus (, plural: nucleoli ) is the largest structure in the nucleus of eukaryotic cells. It is best known as the site of ribosome biogenesis, which is the synthesis of ribosomes. The nucleolus also participates in the formation of s ...

. 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 In eukaryote cells, RNA polymerase III (also called Pol III) is a protein that transcribes DNA to synthesize ribosomal 5S rRNA, tRNA and other small RNAs. The genes transcribed by RNA Pol III fall in the category of "housekeeping" genes whose ...

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. 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. 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.

Structure

The PNC is a dynamic and irregular structure composed of multiple dense strands found primarily in transformed cancer cells. Electron microscopy on

HeLa HeLa (; also Hela or hela) is an immortalized cell line used in scientific research. It is the oldest and most commonly used human cell line. The line is derived from cervical cancer cells taken on February 8, 1951, named after Henrietta ...

cells confirmed that the thick strands are 0.25 - 4 µm in length and 80 - 180 nm in diameter. 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 Ribonuclease (commonly abbreviated RNase) is a type of nuclease that catalyzes the degradation of RNA into smaller components. Ribonucleases can be divided into endoribonucleases and exoribonucleases, and comprise several sub-classes within th ...

, but not

DNase Deoxyribonuclease (DNase, for short) refers to a group of glycoprotein endonucleases which are enzymes that catalyze the hydrolytic cleavage of phosphodiester linkages in the DNA backbone, thus degrading DNA. The role of the DNase enzyme in cell ...

, destroys the PNC establishing the importance of RNA to the structure. 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. 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 S phase (Synthesis Phase) is the phase of the cell cycle in which DNA is replicated, occurring between G1 phase and G2 phase. Since accurate duplication of the genome is critical to successful cell division, the processes that occur during ...

of the cell cycle, the PNC nucleates at a DNA locus and replicates undisturbed with DNA. 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. The PNC is directly proportional to

metastasis Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...

as well as linked to

malignancy Malignancy () is the tendency of a medical condition to become progressively worse. Malignancy is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous ''benign'' tumor in that a malignancy is not s ...

. Thus, it is being further researched in its potential to be a

biomarker In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, p ...

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 Interphase is the portion of the cell cycle that is not accompanied by visible changes under the microscope, and includes the G1, S and G2 phases. During interphase, the cell grows (G1), replicates its DNA (S) and prepares for mitosis (G2). A ...

and mimics the nucleoli during mitosis. In

prophase Prophase () is the first stage of cell division in both mitosis and meiosis. Beginning after interphase, DNA has already been replicated when the cell enters prophase. The main occurrences in prophase are the condensation of the chromatin reti ...

, both gradually deconstruct until reassembly during late

telophase Telophase () is the final stage in both meiosis and mitosis in a eukaryotic cell. During telophase, the effects of prophase and prometaphase (the nucleolus and nuclear membrane disintegrating) are reversed. As chromosomes reach the cell poles, a ...

in the new daughter cell.

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. The PTB and other binding proteins are localized in the PNC to primarily process

RNA polymerase II RNA polymerase II (RNAP II and Pol 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 eukary ...

. In addition, many other small noncoding pol III RNA complexes which regulate pre-rRNA processing are localized in the PNC. 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

blastoma A blastoma is a type of cancer, more common in children, that is caused by malignancies in precursor cells, often called blasts. Examples are nephroblastoma, medulloblastoma, and retinoblastoma. The suffix ''-blastoma'' is used to imply a tumor of ...

carcinoma Carcinoma is a malignancy that develops from epithelial cells. Specifically, a carcinoma is a cancer that begins in a tissue that lines the inner or outer surfaces of the body, and that arises from cells originating in the endodermal, mesoderma ...

s, and

sarcoma A sarcoma is a malignant tumor, a type of cancer that arises from transformed cells of mesenchymal (connective tissue) origin. Connective tissue is a broad term that includes bone, cartilage, fat, vascular, or hematopoietic tissues, and sa ...

s and exclusively represent malignant cells in solid tumor tissues. 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.

References

{{Nucleus, state=collapsed Nuclear substructures