Nucleolus
Overview
The nucleolus is a non-membrane bound structure composed of proteins and nucleic acids found within the nucleus
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...

. Ribosomal RNA
Ribosomal RNA
Ribosomal ribonucleic acid is the RNA component of the ribosome, the enzyme that is the site of protein synthesis in all living cells. Ribosomal RNA provides a mechanism for decoding mRNA into amino acids and interacts with tRNAs during translation by providing peptidyl transferase activity...

 (rRNA) is transcribed
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...

 and assembled within the nucleolus. The nucleolus ultrastructure can be visualized through an electron microscope
Electron microscope
An electron microscope is a type of microscope that uses a beam of electrons to illuminate the specimen and produce a magnified image. Electron microscopes have a greater resolving power than a light-powered optical microscope, because electrons have wavelengths about 100,000 times shorter than...

, while the organization and dynamics can be studied through fluorescent protein tagging
Fluorophore
A fluorophore, in analogy to a chromophore, is a component of a molecule which causes a molecule to be fluorescent. It is a functional group in a molecule which will absorb energy of a specific wavelength and re-emit energy at a different wavelength...

 and fluorescent recovery after photobleaching
Photobleaching
Photobleaching is the photochemical destruction of a fluorophore. In microscopy, photobleaching may complicate the observation of fluorescent molecules, since they will eventually be destroyed by the light exposure necessary to stimulate them into fluorescing...

 (FRAP
Fluorescence recovery after photobleaching
Fluorescence recovery after photobleaching denotes an optical technique capable of quantifying the two dimensional lateral diffusion of a molecularly thin film containing fluorescently labeled probes, or to examine single cells. This technique is very useful in biological studies of cell membrane...

). Malfunction of nucleoli can be the cause for several human diseases.
Encyclopedia
The nucleolus is a non-membrane bound structure composed of proteins and nucleic acids found within the nucleus
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...

. Ribosomal RNA
Ribosomal RNA
Ribosomal ribonucleic acid is the RNA component of the ribosome, the enzyme that is the site of protein synthesis in all living cells. Ribosomal RNA provides a mechanism for decoding mRNA into amino acids and interacts with tRNAs during translation by providing peptidyl transferase activity...

 (rRNA) is transcribed
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...

 and assembled within the nucleolus. The nucleolus ultrastructure can be visualized through an electron microscope
Electron microscope
An electron microscope is a type of microscope that uses a beam of electrons to illuminate the specimen and produce a magnified image. Electron microscopes have a greater resolving power than a light-powered optical microscope, because electrons have wavelengths about 100,000 times shorter than...

, while the organization and dynamics can be studied through fluorescent protein tagging
Fluorophore
A fluorophore, in analogy to a chromophore, is a component of a molecule which causes a molecule to be fluorescent. It is a functional group in a molecule which will absorb energy of a specific wavelength and re-emit energy at a different wavelength...

 and fluorescent recovery after photobleaching
Photobleaching
Photobleaching is the photochemical destruction of a fluorophore. In microscopy, photobleaching may complicate the observation of fluorescent molecules, since they will eventually be destroyed by the light exposure necessary to stimulate them into fluorescing...

 (FRAP
Fluorescence recovery after photobleaching
Fluorescence recovery after photobleaching denotes an optical technique capable of quantifying the two dimensional lateral diffusion of a molecularly thin film containing fluorescently labeled probes, or to examine single cells. This technique is very useful in biological studies of cell membrane...

). Malfunction of nucleoli can be the cause for several human diseases. It takes up to about 25% of the nuclear volume.

Structure

Three major components of the nucleolus are recognized: the fibrillar centers (FC), the dense fibrillar components (DFC), and granular components (GC). The DFC or pars fibrosa consists of newly transcribed rRNA bound to ribosomal proteins, while the GC, called pars granulosa, contains rRNA bound to ribosomal proteins that are beginning to assemble into ribosome
Ribosome
A ribosome is a component of cells that assembles the twenty specific amino acid molecules to form the particular protein molecule determined by the nucleotide sequence of an RNA molecule....

s. However, it has been proposed that this particular organization is only observed in higher eukaryotes and that it evolved from a bipartite organization with the transition from anamniotes
Anamniotes
The anamniotes are an informal group of vertebrates that lack the amnion during fetal development. These animals are not able to have embryos that develop on land, thus they lay their eggs in water exclusively...

 to amniote
Amniote
The amniotes are a group of tetrapods that have a terrestrially adapted egg. They include synapsids and sauropsids , as well as their fossil ancestors. Amniote embryos, whether laid as eggs or carried by the female, are protected and aided by several extensive membranes...

s. Reflecting the substantial increase in the DNA intergenic region
Intergenic region
An Intergenic region is a stretch of DNA sequences located between clusters of genes that contain few or no genes. Occasionally some intergenic DNA acts to control genes nearby, but most of it has no currently known function...

, an original fibrillar component would have separated into the FC and the DFC. Another structure identified within many nucleoli (particularly in plants) is a clear area in the center of the structure referred to as a nucleolar vacuole.

Function and ribosome assembly

Nucleoli are formed around specific genetic loci
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...

  called nucleolar organizing regions (NORs), first described by Barbara McClintock
Barbara McClintock
Barbara McClintock , the 1983 Nobel Laureate in Physiology or Medicine, was an American scientist and one of the world's most distinguished cytogeneticists. McClintock received her PhD in botany from Cornell University in 1927, where she was a leader in the development of maize cytogenetics...

. Because of this non-random organization, the nucleolus is defined as a "genetically determined element." A NOR is composed of tandem repeats of rRNA genes, which can be found in several different chromosomes. The human genome, for example, contains more than 200 clustered copies of the rRNA genes on five different chromosomes (13, 14, 15, 21, 22). In a typical eukaryote, a rRNA gene consists of a promoter, internal and external transcribed spacers (ITS
Internal transcribed spacer
ITS refers to a piece of non-functional RNA situated between structural ribosomal RNAs on a common precursor transcript. Read from 5' to 3', this polycistronic rRNA precursor transcript contains the 5' external transcribed sequence , 18S rRNA, ITS1, 5.8S rRNA, ITS2, 28S rRNA and finally the 3'ETS...

/ETS
External transcribed spacer
External transcribed spacer refers to a piece of non-functional RNA, closely related to the internal transcribed spacer, which is situated outside structural ribosomal RNAs on a common precursor transcript....

), rRNA coding sequences (18S, 5.8S, 28S) and an external non-transcribed spacer.
In ribosome biogenesis, two of the three eukaryotic RNA polymerase
RNA polymerase
RNA polymerase is an enzyme that produces RNA. In cells, RNAP is needed for constructing RNA chains from DNA genes as templates, a process called transcription. RNA polymerase enzymes are essential to life and are found in all organisms and many viruses...

s (pol I and III) are required, and these function in a coordinated manner. In an initial stage, the rRNA genes are transcribed as a single unit within the nucleolus by RNA pol I or III. In order for this transcription to occur, several pol I-associated factors and DNA-specific transacting factors are required. In yeast
Yeast
Yeasts are eukaryotic micro-organisms classified in the kingdom Fungi, with 1,500 species currently described estimated to be only 1% of all fungal species. Most reproduce asexually by mitosis, and many do so by an asymmetric division process called budding...

, the most important are: UAF (upstream activating factor), TBP
TATA Binding Protein
The TATA-binding protein is a general transcription factor that binds specifically to a DNA sequence called the TATA box. This DNA sequence is found about 35 base pairs upstream of the transcription start site in some eukaryotic gene promoters...

 (tata-box binding protein), and CF (core factor), which bind promoter elements and form the preinitiation complex
Preinitiation complex
The preinitiation complex is a large complex of proteins that is necessary for the transcription of protein-coding genes in eukaryotes...

 (PIC), which is in turn recognized by RNA pol. In humans, a similar PIC is assembled with SLI, the promoter selectivity factor (composed of TBP and TBP-associated factors, or TAFs), IF
Initiation factor
Initiation factors are proteins that bind to the small subunit of the ribosome during the initiation of translation, a part of protein biosynthesis.They are divided into three major groups:*Prokaryotic initiation factors*Archaeal initiation factors...

s (transcription initiation factors) and UBF (upstream binding factor). RNA polymerase I transcribes most rRNA transcripts (28S, 18S, and 5.8S) but the 5S rRNA subunit (component of the 60S ribosomal subunit) is transcribed by RNA polymerase III.

Transcription of the ribosomal gene yields a long precursor molecule (45S pre-rRNA) which still contains the ITS and ETS. Further processing is needed to generate the 18S RNA, 5.8S and 28S RNA molecules. In eukaryotes, the RNA-modifying enzymes are brought to their respective recognition sites by interaction with guide RNAs, which bind these specific sequences. These guide RNAs belong to the class of small nucleolar RNAs (snoRNA
SnoRNA
Small nucleolar RNAs are a class of small RNA molecules that primarily guide chemical modifications of other RNAs, mainly ribosomal RNAs, transfer RNAs and small nuclear RNAs...

s) which are complexed with proteins and exist as small-nucleolar-ribonucleoprotein
Ribonucleoprotein
Ribonucleoprotein is a nucleoprotein that contains RNA, i.e. it is an association that combines ribonucleic acid and protein together. A few known examples include the ribosome, the enzyme telomerase, vault ribonucleoproteins, and small nuclear RNPs , which are implicated in pre-mRNA splicing and...

s (snoRNPs). Once the rRNA subunits are processed, they are ready to be assembled into larger ribosomal subunits. However, an additional rRNA molecule, the 5S rRNA, is also necessary. In yeast, the 5S rDNA sequence is localized in the external non-transcribed spacer and is transcribed in the nucleolus by RNA pol. In higher eukaryote
Eukaryote
A eukaryote is an organism whose cells contain complex structures enclosed within membranes. Eukaryotes may more formally be referred to as the taxon Eukarya or Eukaryota. The defining membrane-bound structure that sets eukaryotic cells apart from prokaryotic cells is the nucleus, or nuclear...

s and plants, the situation is more complex, for the 5S DNA sequence lies outside the NOR and is transcribed by RNA pol III in the nucleoplasm
Nucleoplasm
Similar to the cytoplasm of a cell, the nucleus contains nucleoplasm or karyoplasm. The nucleoplasm is one of the types of protoplasm, and it is enveloped by the nuclear membrane or nuclear envelope. The nucleoplasm is a highly viscous liquid that surrounds the chromosomes and nucleoli...

, after which it finds its way into the nucleolus to participate in the ribosome assembly. This assembly not only involves the rRNA, but ribosomal proteins as well. The genes encoding these r-proteins are transcribed by pol II in the nucleoplasm by a "conventional" pathway of protein synthesis (transcription, pre-mRNA processing, nuclear export of mature mRNA and translation on cytoplasmic ribosomes). The mature r-proteins are then "imported" back into the nucleus and finally the nucleolus. Association and maturation of rRNA and r-proteins result in the formation of the 40S (small) and 60S (large) subunits of the complete ribosome. These are exported through the nuclear pore complexes to the cytoplasm, where they remain free or become associated with the endoplasmic reticulum
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...

, forming rough endoplasmic reticulum (RER).

A continuous chain between the nucleoplasm and the inner parts of the nucleolus exists through a network of nucleolar channels. In this way, macromolecules with a molecular weight up to 2000 kDa
KDA
KDA may refer to:* Karachi Development Authority* Kongsberg Defence & Aerospace* Kotelawala Defence Academy* Kramer Design Associates* Lithium diisopropylamide, KDA is the potassium analogue of lithium diisopropylamideOr kDa may refer to:...

are easily distributed throughout the nucleolus.

External links

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