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Small nuclear RNA (snRNA) is a class of
small RNA Small RNA (sRNA) are polymeric RNA molecules that are less than 200 nucleotides in length, and are usually non-coding. RNA silencing is often a function of these molecules, with the most common and well-studied example being RNA interference (RNA ...
molecules that are found within the
splicing speckles The cell nucleus (pl. nuclei; from Latin or , meaning ''kernel'' or ''seed'') is a membrane-bound organelle found in eukaryotic cells. Eukaryotic cells usually have a single nucleus, but a few cell types, such as mammalian red blood cells, ha ...
and
Cajal bodies Cajal bodies (CBs) also coiled bodies, are spherical nuclear bodies of 0.3–1.0 µm in diameter found in the nucleus of proliferative cells like embryonic cells and tumor cells, or metabolically active cells like neurons. CBs are membrane-l ...
of the
cell nucleus The cell nucleus (pl. nuclei; from Latin or , meaning ''kernel'' or ''seed'') is a membrane-bound organelle found in eukaryotic cells. Eukaryotic cells usually have a single nucleus, but a few cell types, such as mammalian red blood cells, h ...
in
eukaryotic Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bact ...
cells. The length of an average snRNA is approximately 150 nucleotides. They are transcribed by either
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 eukaryotic ...
or
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 e ...
. Their primary function is in the processing of pre-
messenger RNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein. mRNA is created during the p ...
(
hnRNA 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 a ...
) in the nucleus. They have also been shown to aid in the regulation of
transcription factors In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fun ...
(
7SK RNA In molecular biology 7SK is an abundant small nuclear RNA found in metazoans. It plays a role in regulating transcription by controlling the positive transcription elongation factor P-TEFb. 7SK is found in a small nuclear ribonucleoprotein ...
) or RNA polymerase II (B2 RNA), and maintaining the
telomere A telomere (; ) is a region of repetitive nucleotide sequences associated with specialized proteins at the ends of linear chromosomes. Although there are different architectures, telomeres, in a broad sense, are a widespread genetic feature mo ...
s. snRNA are always associated with a set of specific proteins, and the complexes are referred to as small nuclear ribonucleoproteins (
snRNP snRNPs (pronounced "snurps"), or small nuclear ribonucleoproteins, are RNA-protein complexes that combine with unmodified pre-mRNA and various other proteins to form a spliceosome, a large RNA-protein molecular complex upon which splicing of pre-m ...
, often pronounced "snurps"). Each snRNP particle is composed of a snRNA component and several snRNP-specific proteins (including Sm proteins, a family of nuclear proteins). The most common human snRNA components of these complexes are known, respectively, as:
U1 spliceosomal RNA U1 spliceosomal RNA is the small nuclear RNA (snRNA) component of U1 snRNP (''small nuclear ribonucleoprotein''), an RNA-protein complex that combines with other snRNPs, unmodified pre-mRNA, and various other proteins to assemble a spliceosome, a ...
,
U2 spliceosomal RNA U2 spliceosomal snRNAs are a species of small nuclear RNA (snRNA) molecules found in the major spliceosomal (Sm) machinery of virtually all eukaryotic organisms. ''In vivo'', U2 snRNA along with its associated polypeptides assemble to produce the ...
,
U4 spliceosomal RNA The U4 small nuclear Ribo-Nucleic Acid (U4 snRNA) is a non-coding RNA component of the major or U2-dependent spliceosome – a eukaryotic molecular machine involved in the splicing of pre-messenger RNA (pre-mRNA). It forms a duplex with U6, an ...
,
U5 spliceosomal RNA U5 snRNA is a small nuclear RNA (snRNA) that participates in RNA splicing as a component of the spliceosome. It forms the U5 snRNP (''small nuclear ribonucleoprotein'') by associating with several proteins including Prp8 - the largest and most co ...
, and
U6 spliceosomal RNA U6 snRNA is the non-coding small nuclear RNA (snRNA) component of U6 snRNP (''small nuclear ribonucleoprotein''), an RNA-protein complex that combines with other snRNPs, unmodified pre-mRNA, and various other proteins to assemble a spliceosome, a ...
. Their nomenclature derives from their high
uridine Uridine (symbol U or Urd) is a glycosylated pyrimidine analog containing uracil attached to a ribose ring (or more specifically, a ribofuranose) via a β-N1-glycosidic bond. The analog is one of the five standard nucleosides which make up nucle ...
content. snRNAs were discovered by accident during a
gel electrophoresis Gel electrophoresis is a method for separation and analysis of biomacromolecules ( DNA, RNA, proteins, etc.) and their fragments, based on their size and charge. It is used in clinical chemistry to separate proteins by charge or size (IEF ...
experiment in 1966. An unexpected type of RNA was found in the gel and investigated. Later analysis has shown that these RNA were high in uridylate and were established in the nucleus. snRNAs and
small nucleolar RNA In molecular biology, Small nucleolar RNAs (snoRNAs) are a class of small RNA molecules that primarily guide chemical modifications of other RNAs, mainly ribosomal RNAs, transfer RNAs and small nuclear RNAs. There are two main classes of snoRNA, t ...
s (snoRNAs) are not the same and neither is a subtype of the other. Both are different and are a class under small RNAs. These are small RNA molecules that play an essential role in RNA biogenesis and guide chemical modifications of ribosomal RNAs (rRNAs) and other RNA genes (tRNA and snRNAs). They are located in 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 sig ...
and the
Cajal bodies Cajal bodies (CBs) also coiled bodies, are spherical nuclear bodies of 0.3–1.0 µm in diameter found in the nucleus of proliferative cells like embryonic cells and tumor cells, or metabolically active cells like neurons. CBs are membrane-l ...
of
eukaryotic Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bact ...
cells (the major sites of RNA synthesis), where they are called
scaRNA Scarna is a village in Tuscany, central Italy, in the comune of Colle di Val d'Elsa, province of Siena. At the time of the 2001 census its population was 56.LSm proteins. The first class, known as Sm-class snRNA, is more widely studied and consists of U1, U2, U4, U4atac, U5, U7, U11, and U12. Sm-class snRNA are transcribed by
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 eukaryotic ...
. The pre-snRNA are transcribed and receive the usual 7-methylguanosine
five-prime cap In molecular biology, the five-prime cap (5′ cap) is a specially altered nucleotide on the 5′ end of some primary transcripts such as precursor messenger RNA. This process, known as mRNA capping, is highly regulated and vital in the creation of ...
in the
nucleus Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to: *Atomic nucleus, the very dense central region of an atom *Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA Nucle ...
. They are then exported to the cytoplasm through
nuclear pores A nuclear pore is a part of a large complex of proteins, known as a nuclear pore complex that spans the nuclear envelope, which is the double membrane surrounding the eukaryotic cell nucleus. There are approximately 1,000 nuclear pore complexes ...
for further processing. In the cytoplasm, the snRNA receive 3′ trimming to form a 3′ stem-loop structure, as well as hypermethylation of the 5′ cap to form trimethylguanosine. The 3′ stem structure is necessary for recognition by the
survival of motor neuron Survival of motor neuron or survival motor neuron (SMN) is a protein that in humans is encoded by the ''SMN1'' and ''SMN2'' genes. SMN is found in the cytoplasm of all animal cells and also in the nuclear gems. It functions in transcriptional re ...
(SMN) protein. This complex assembles the snRNA into stable ribonucleoproteins (RNPs). The modified 5′ cap is then required to import the snRNP back into the nucleus. All of these uridine-rich snRNA, with the exception of U7, form the core of the
spliceosome A spliceosome is a large ribonucleoprotein (RNP) complex found primarily within the nucleus of eukaryotic cells. The spliceosome is assembled from small nuclear RNAs (snRNA) and numerous proteins. Small nuclear RNA (snRNA) molecules bind to specifi ...
. Splicing, or the removal of
intron An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e. a region inside a gene."The notion of the cistron .e., gene. ...
s, is a major aspect of post-transcriptional modification, and takes place only in the nucleus of eukaryotes. U7 snRNA has been found to function in
histone In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn are ...
pre-mRNA processing. The second class, known as Lsm-class snRNA, consists of U6 and U6atac. Lsm-class snRNAs are transcribed by
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 e ...
and never leave the nucleus, in contrast to Sm-class snRNA. Lsm-class snRNAs contain a 5′-γ-monomethylphosphate cap and a 3′ stem–loop, terminating in a stretch of uridines that form the binding site for a distinct heteroheptameric ring of Lsm proteins.


In the spliceosome

Spliceosomes catalyse splicing, an integral step in eukaryotic precursor messenger RNA maturation. A splicing mistake in even a single
nucleotide Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules with ...
can be devastating to the cell, and a reliable, repeatable method of RNA processing is necessary to ensure cell survival. The spliceosome is a large, protein-RNA complex that consists of five small nuclear RNAs (U1, U2, U4, U5, and U6) and over 150 proteins. The snRNAs, along with their associated proteins, form ribonucleoprotein complexes (snRNPs), which bind to specific sequences on the
pre-mRNA 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 ...
substrate. This intricate process results in two sequential transesterification reactions. These reactions will produce a free lariat intron and ligate two exons to form a mature mRNA. There are two separate classes of spliceosomes. The major class, which is far more abundant in eukaryotic cells, splices primarily U2-type introns. The initial step of splicing is the bonding of the U1 snRNP and its associated proteins to the 5’ splice end to the
hnRNA 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 a ...
. This creates the commitment complex which will constrain the hnRNA to the splicing pathway. Then, U2 snRNP is recruited to the spliceosome binding site and forms complex A, after which the U5.U4/U6 tri-snRNP complex binds to complex A to form the structure known as complex B. After rearrangement, complex C is formed, and the spliceosome is active for catalysis. In the catalytically active spliceosome U2 and U6 snRNAs fold to form a conserved structure called the catalytic triplex. This structure coordinates two magnesium ions that form the active site of the spliceosome. This is an example of RNA catalysis. In addition to this main spliceosome complex, there exists a much less common (~1%) minor spliceosome. This complex comprises U11, U12, U4atac, U6atac and U5 snRNPs. These snRNPs are functional analogs of the snRNPs used in the major spliceosome. The minor spliceosome splices U12-type introns. The two types of introns mainly differ in their splicing sites: U2-type introns have GT-AG 5′ and 3′ splice sites while U12-type introns have AT-AC at their 5′ and 3′ ends. The minor spliceosome carries out its function through a different pathway from the major spliceosome.


U1 snRNA

U1 snRNP is the initiator of spliceosomal activity in the cell by base pairing with the 5′ splice site of the pre-mRNA. In the major spliceosome, experimental data has shown that the U1 snRNP is present in equal stoichiometry with U2, U4, U5, and U6 snRNP. However, U1 snRNP's abundance in human cells is far greater than that of the other snRNPs. Through U1 snRNA
gene knockdown Gene knockdown is an experimental technique by which the expression of one or more of an organism's genes is reduced. The reduction can occur either through genetic modification or by treatment with a reagent such as a short DNA or RNA oligonucleot ...
in
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 L ...
cells, studies have shown the U1 snRNA holds great importance for cellular function. When U1 snRNA genes were knocked out, genomic microarrays showed an increased accumulation of unspliced pre-mRNA. In addition, the knockout was shown to cause premature cleavage and
polyadenylation Polyadenylation is the addition of a poly(A) tail to an RNA transcript, typically a messenger RNA (mRNA). The poly(A) tail consists of multiple adenosine monophosphates; in other words, it is a stretch of RNA that has only adenine bases. In euk ...
primarily in introns located near the beginning of the transcript. When other uridine based snRNAs were knocked out, this effect was not seen. Thus, U1 snRNA–pre-mRNA base pairing was shown to protect pre-mRNA from polyadenylation as well as premature cleavage. This special protection may explain the overabundance of U1 snRNA in the cell.


snRNPs and human disease

Through the study of small nuclear ribonucleoproteins (snRNPs) and small nucleolar (sno)RNPs we have been able to better understand many important diseases. Spinal muscular atrophy - Mutations in the survival motor neuron-1 (SMN1) gene result in the degeneration of spinal
motor neurons A motor neuron (or motoneuron or efferent neuron) is a neuron whose cell body is located in the motor cortex, brainstem or the spinal cord, and whose axon (fiber) projects to the spinal cord or outside of the spinal cord to directly or indirectly ...
and severe muscle wasting. The SMN protein assembles Sm-class snRNPs, and probably also snoRNPs and other RNPs. Spinal muscular atrophy affects up to 1 in 6,000 people and is the second leading cause of
neuromuscular A neuromuscular junction (or myoneural junction) is a chemical synapse between a motor neuron and a muscle fiber. It allows the motor neuron to transmit a signal to the muscle fiber, causing muscle contraction. Muscles require innervation to ...
disease, after
Duchenne muscular dystrophy Duchenne muscular dystrophy (DMD) is a severe type of muscular dystrophy that primarily affects boys. Muscle weakness usually begins around the age of four, and worsens quickly. Muscle loss typically occurs first in the thighs and pelvis follow ...
.
Dyskeratosis congenita Dyskeratosis congenita (DKC), also known as Zinsser-Engman-Cole syndrome, is a rare progressive congenital disorder with a highly variable phenotype. The entity was classically defined by the triad of abnormal skin pigmentation, nail dystrophy, an ...
– Mutations in the assembled snRNPs are also found to be a cause of dyskeratosis congenita, a rare syndrome that presents by abnormal changes in the skin, nails and mucous membrane. Some ultimate effects of this disease include bone-marrow failure as well as cancer. This syndrome has been shown to arise from mutations in multiple genes, including
dyskerin H/ACA ribonucleoprotein complex subunit 4 is a protein that in humans is encoded by the gene ''DKC1''. This gene is a member of the H/ACA snoRNPs (small nucleolar ribonucleoproteins) gene family. snoRNPs are involved in various aspects of rRNA ...
,
telomerase RNA Telomerase RNA component, also known as TR, TER or TERC, is an ncRNA found in eukaryotes that is a component of telomerase, the enzyme used to extend telomeres. TERC serves as a template for telomere replication (reverse transcription) by te ...
and
telomerase reverse transcriptase Telomerase reverse transcriptase (abbreviated to TERT, or hTERT in humans) is a catalytic subunit of the enzyme telomerase, which, together with the telomerase RNA component (TERC), comprises the most important unit of the telomerase complex. ...
.
Prader–Willi syndrome Prader–Willi syndrome (PWS) is a genetic disorder caused by a loss of function of specific genes on chromosome 15. In newborns, symptoms include weak muscles, poor feeding, and slow development. Beginning in childhood, those affected become c ...
– This syndrome affects as many as 1 in 12,000 people and has a presentation of extreme hunger, cognitive and behavioural problems, poor muscle tone and short stature. The syndrome has been linked to the deletion of a region of paternal chromosome 15 that is not expressed on the maternal chromosome. This region includes a brain-specific snRNA that targets the
serotonin Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vas ...
-2C receptor
mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein. mRNA is created during the p ...
.
Medulloblastoma Medulloblastoma is a common type of primary brain cancer in children. It originates in the part of the brain that is towards the back and the bottom, on the floor of the skull, in the cerebellum, or posterior fossa. The brain is divided into tw ...
– The U1 snRNA is mutated in a subset of these
brain tumor A brain tumor occurs when abnormal cells form within the brain. There are two main types of tumors: malignant tumors and benign (non-cancerous) tumors. These can be further classified as primary tumors, which start within the brain, and seconda ...
s, and leads to altered
RNA splicing RNA splicing is a process in molecular biology where a newly-made precursor messenger RNA (pre-mRNA) transcript is transformed into a mature messenger RNA (mRNA). It works by removing all the introns (non-coding regions of RNA) and ''splicing'' b ...
. The mutations predominantly occur in adult tumors, and are associated with poor prognosis.


Post-transcriptional modification

In
eukaryotes Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bact ...
, snRNAs contain a significant amount of
2′-O-methylation 2'-''O''-methylation is a common nucleoside modification of RNA, where a methyl group is added to the 2' hydroxyl of the ribose moiety of a nucleoside, producing a methoxy group. 2'-''O''-methylated nucleosides are mostly found in ribosomal RNA a ...
modifications and pseudouridylations. These modifications are associated with
snoRNA In molecular biology, Small nucleolar RNAs (snoRNAs) are a class of small RNA molecules that primarily guide chemical modifications of other RNAs, mainly ribosomal RNAs, transfer RNAs and small nuclear RNAs. There are two main classes of snoRNA, t ...
activity which canonically modify pre-mature rRNAs but have been observed in modifying other cellular RNA targets such as snRNAs. Finally, oligo-adenylation (short poly(A)tailing) can determine the fate of snRNAs (that are usually not poly(A)-tailed) and thereby induce their RNA decay. This mechanism regulating the abundance of snRNAs is in turn coupled to a widespread change of alternative RNA splicing.


See also

*
MicroRNA MicroRNA (miRNA) are small, single-stranded, non-coding RNA molecules containing 21 to 23 nucleotides. Found in plants, animals and some viruses, miRNAs are involved in RNA silencing and post-transcriptional regulation of gene expression. miRN ...


References


External links

* * {{Nucleic acids RNA Molecular genetics Non-coding RNA Telomeres