Small nuclear RNA

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Small nuclear RNA (snRNA) is a class of small RNA molecules that are found within the splicing speckles and Cajal bodies of the cell nucleus in eukaryotic cells. The length of an average snRNA is approximately 150 nucleotides. They are transcribed by either RNA polymerase II or RNA polymerase III. [1] Their primary function is in the processing of pre-messenger RNA (hnRNA) in the nucleus. They have also been shown to aid in the regulation of transcription factors (7SK RNA) or RNA polymerase II (B2 RNA), and maintaining the telomeres.

Contents

snRNA are always associated with a set of specific proteins, and the complexes are referred to as small nuclear ribonucleoproteins (snRNP, 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, U2 spliceosomal RNA, U4 spliceosomal RNA, U5 spliceosomal RNA, and U6 spliceosomal RNA. Their nomenclature derives from their high uridine content.

snRNAs were discovered by accident during a gel electrophoresis experiment in 1966. [2] 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 RNAs (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 and the Cajal bodies of eukaryotic cells (the major sites of RNA synthesis), where they are called scaRNAs (small Cajal body-specific RNAs).

Classes

snRNA are often divided into two classes based upon both common sequence features as well as associated protein factors such as the RNA-binding LSm proteins. [3]

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. The pre-snRNA are transcribed and receive the usual 7-methylguanosine five-prime cap in the nucleus. They are then exported to the cytoplasm through nuclear pores 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. [4] The 3′ stem structure is necessary for recognition by the survival of motor neuron (SMN) protein. [5] 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. Splicing, or the removal of introns, 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 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 and never leave the nucleus, in contrast to Sm-class snRNA. Lsm-class snRNAs contain a 5′-γ-monomethylphosphate cap [6] and a 3′ stem–loop, terminating in a stretch of uridines that form the binding site for a distinct heteroheptameric ring of Lsm proteins. [7]

In the spliceosome

A comparison between major and minor splicing mechanisms Minor spliceosome.jpg
A comparison between major and minor splicing mechanisms

Spliceosomes catalyse splicing, an integral step in eukaryotic precursor messenger RNA maturation. A splicing mistake in even a single nucleotide 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 substrate. [8] 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. This creates the commitment complex which will constrain the hnRNA to the splicing pathway. [9] 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. [10] In the catalytically active spliceosome U2 and U6 snRNAs fold to form a conserved structure called the catalytic triplex. [11] This structure coordinates two magnesium ions that form the active site of the spliceosome. [12] [13] 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

Predicted secondary structure and sequence conservation of U1 snRNA RF00003.jpg
Predicted secondary structure and sequence conservation of 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. [14] Through U1 snRNA gene knockdown in HeLa 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. [15] In addition, the knockout was shown to cause premature cleavage and polyadenylation 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 and severe muscle wasting. The SMN protein assembles Sm-class snRNPs, and probably also snoRNPs and other RNPs. [16] Spinal muscular atrophy affects up to 1 in 6,000 people and is the second leading cause of neuromuscular disease, after Duchenne muscular dystrophy. [17]

Dyskeratosis congenita – 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, telomerase RNA and telomerase reverse transcriptase. [18]

Prader–Willi syndrome – 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. [19] 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-2C receptor mRNA.

Medulloblastoma – The U1 snRNA is mutated in a subset of these brain tumors, and leads to altered RNA splicing. [20] The mutations predominantly occur in adult tumors, and are associated with poor prognosis.

Post-transcriptional modification

In eukaryotes, snRNAs contain a significant amount of 2′-O-methylation modifications and pseudouridylations. [21] These modifications are associated with snoRNA 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. [22] This mechanism regulating the abundance of snRNAs is in turn coupled to a widespread change of alternative RNA splicing.

See also

Related Research Articles

<span class="mw-page-title-main">RNA splicing</span> Process in molecular biology

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 and splicing back together exons. For nuclear-encoded genes, splicing occurs in the nucleus either during or immediately after transcription. For those eukaryotic genes that contain introns, splicing is usually needed to create an mRNA molecule that can be translated into protein. For many eukaryotic introns, splicing occurs in a series of reactions which are catalyzed by the spliceosome, a complex of small nuclear ribonucleoproteins (snRNPs). There exist self-splicing introns, that is, ribozymes that can catalyze their own excision from their parent RNA molecule. The process of transcription, splicing and translation is called gene expression, the central dogma of molecular biology.

<span class="mw-page-title-main">Spliceosome</span> Molecular machine that removes intron RNA from the primary transcript

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 specific proteins to form a small nuclear ribonucleoprotein complex, which in turn combines with other snRNPs to form a large ribonucleoprotein complex called a spliceosome. The spliceosome removes introns from a transcribed pre-mRNA, a type of primary transcript. This process is generally referred to as splicing. An analogy is a film editor, who selectively cuts out irrelevant or incorrect material from the initial film and sends the cleaned-up version to the director for the final cut.

snRNPs, 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-mRNA occurs. The action of snRNPs is essential to the removal of introns from pre-mRNA, a critical aspect of post-transcriptional modification of RNA, occurring only in the nucleus of eukaryotic cells. Additionally, U7 snRNP is not involved in splicing at all, as U7 snRNP is responsible for processing the 3′ stem-loop of histone pre-mRNA.

<span class="mw-page-title-main">Minor spliceosome</span>

The minor spliceosome is a ribonucleoprotein complex that catalyses the removal (splicing) of an atypical class of spliceosomal introns (U12-type) from messenger RNAs in some clades of eukaryotes. This process is called noncanonical splicing, as opposed to U2-dependent canonical splicing. U12-type introns represent less than 1% of all introns in human cells. However they are found in genes performing essential cellular functions.

<span class="mw-page-title-main">LSm</span> Family of RNA-binding proteins

In molecular biology, LSm proteins are a family of RNA-binding proteins found in virtually every cellular organism. LSm is a contraction of 'like Sm', because the first identified members of the LSm protein family were the Sm proteins. LSm proteins are defined by a characteristic three-dimensional structure and their assembly into rings of six or seven individual LSm protein molecules, and play a large number of various roles in mRNA processing and regulation.

<span class="mw-page-title-main">U11 spliceosomal RNA</span> Non-coding RNA involved in alternative splicing

The U11 snRNA is an important non-coding RNA in the minor spliceosome protein complex, which activates the alternative splicing mechanism. The minor spliceosome is associated with similar protein components as the major spliceosome. It uses U11 snRNA to recognize the 5' splice site while U12 snRNA binds to the branchpoint to recognize the 3' splice site.

<span class="mw-page-title-main">U1 spliceosomal RNA</span>

U1 spliceosomal RNA is the small nuclear RNA (snRNA) component of U1 snRNP, an RNA-protein complex that combines with other snRNPs, unmodified pre-mRNA, and various other proteins to assemble a spliceosome, a large RNA-protein molecular complex upon which splicing of pre-mRNA occurs. Splicing, or the removal of introns, is a major aspect of post-transcriptional modification, and takes place only in the nucleus of eukaryotes.

<span class="mw-page-title-main">U2 spliceosomal RNA</span>

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 U2 small nuclear ribonucleoprotein (snRNP), an essential component of the major spliceosomal complex. The major spliceosomal-splicing pathway is occasionally referred to as U2 dependent, based on a class of Sm intron—found in mRNA primary transcripts—that are recognized exclusively by the U2 snRNP during early stages of spliceosomal assembly. In addition to U2 dependent intron recognition, U2 snRNA has been theorized to serve a catalytic role in the chemistry of pre-RNA splicing as well. Similar to ribosomal RNAs (rRNAs), Sm snRNAs must mediate both RNA:RNA and RNA:protein contacts and hence have evolved specialized, highly conserved, primary and secondary structural elements to facilitate these types of interactions.

<span class="mw-page-title-main">U4 spliceosomal RNA</span> Non-coding RNA component of the spliceosome

The U4 small nuclear Ribo-Nucleic Acid 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, and with each splicing round, it is displaced from the U6 snRNA in an ATP-dependent manner, allowing U6 to re-fold and create the active site for splicing catalysis. A recycling process involving protein Brr2 releases U4 from U6, while protein Prp24 re-anneals U4 and U6. The crystal structure of a 5′ stem-loop of U4 in complex with a binding protein has been solved.

<span class="mw-page-title-main">U5 spliceosomal RNA</span>

U5 snRNA is a small nuclear RNA (snRNA) that participates in RNA splicing as a component of the spliceosome. It forms the U5 snRNP by associating with several proteins including Prp8 - the largest and most conserved protein in the spliceosome, Brr2 - a helicase required for spliceosome activation, Snu114, and the 7 Sm proteins. U5 snRNA forms a coaxially-stacked series of helices that project into the active site of the spliceosome. Loop 1, which caps this series of helices, forms 4-5 base pairs with the 5'-exon during the two chemical reactions of splicing. This interaction appears to be especially important during step two of splicing, exon ligation.

<span class="mw-page-title-main">U6 spliceosomal RNA</span> Small nuclear RNA component of the spliceosome

U6 snRNA is the non-coding small nuclear RNA (snRNA) component of U6 snRNP, an RNA-protein complex that combines with other snRNPs, unmodified pre-mRNA, and various other proteins to assemble a spliceosome, a large RNA-protein molecular complex that catalyzes the excision of introns from pre-mRNA. Splicing, or the removal of introns, is a major aspect of post-transcriptional modification and takes place only in the nucleus of eukaryotes.

<span class="mw-page-title-main">Small Cajal body-specific RNA</span>

Small Cajal body-specific RNAs (scaRNAs) are a class of small nucleolar RNAs (snoRNAs) that specifically localise to the Cajal body, a nuclear organelle involved in the biogenesis of small nuclear ribonucleoproteins. ScaRNAs guide the modification of RNA polymerase II transcribed spliceosomal RNAs U1, U2, U4, U5 and U12.

<span class="mw-page-title-main">SNRPB</span> Protein-coding gene in the species Homo sapiens

Small nuclear ribonucleoprotein-associated proteins B and B' is a protein that in humans is encoded by the SNRPB gene.

<span class="mw-page-title-main">Small nuclear ribonucleoprotein D2</span> Protein-coding gene in the species Homo sapiens

Small nuclear ribonucleoprotein Sm D2 is a protein that in humans is encoded by the SNRPD2 gene. It belongs to the small nuclear ribonucleoprotein core protein family, and is required for pre-mRNA splicing and small nuclear ribonucleoprotein biogenesis. Alternative splicing occurs at this locus and two transcript variants encoding the same protein have been identified.

<span class="mw-page-title-main">SNRPB2</span> Protein-coding gene in the species Homo sapiens

U2 small nuclear ribonucleoprotein B is a protein that in humans is encoded by the SNRPB2 gene.

<span class="mw-page-title-main">PRPF4</span> Protein-coding gene in the species Homo sapiens

U4/U6 small nuclear ribonucleoprotein Prp4 is a protein that in humans is encoded by the PRPF4 gene. The removal of introns from nuclear pre-mRNAs occurs on complexes called spliceosomes, which are made up of 4 small nuclear ribonucleoprotein (snRNP) particles and an undefined number of transiently associated splicing factors. PRPF4 is 1 of several proteins that associate with U4 and U6 snRNPs.[supplied by OMIM]

<span class="mw-page-title-main">Prp24</span>

Prp24 is a protein part of the pre-messenger RNA splicing process and aids the binding of U6 snRNA to U4 snRNA during the formation of spliceosomes. Found in eukaryotes from yeast to E. coli, fungi, and humans, Prp24 was initially discovered to be an important element of RNA splicing in 1989. Mutations in Prp24 were later discovered in 1991 to suppress mutations in U4 that resulted in cold-sensitive strains of yeast, indicating its involvement in the reformation of the U4/U6 duplex after the catalytic steps of splicing.

<span class="mw-page-title-main">Prp8</span>

Prp8 refers to both the Prp8 protein and Prp8 gene. Prp8's name originates from its involvement in pre-mRNA processing. The Prp8 protein is a large, highly conserved, and unique protein that resides in the catalytic core of the spliceosome and has been found to have a central role in molecular rearrangements that occur there. Prp8 protein is a major central component of the catalytic core in the spliceosome, and the spliceosome is responsible for splicing of precursor mRNA that contains introns and exons. Unexpressed introns are removed by the spliceosome complex in order to create a more concise mRNA transcript. Splicing is just one of many different post-transcriptional modifications that mRNA must undergo before translation. Prp8 has also been hypothesized to be a cofactor in RNA catalysis.

Christine Guthrie (1945-2022) was an American yeast geneticist and American Cancer Society Research Professor of Genetics at University of California San Francisco. She showed that yeast have small nuclear RNAs (snRNAs) involved in splicing pre-messenger RNA into messenger RNA in eukaryotic cells. Guthrie cloned and sequenced the genes for yeast snRNA and established the role of base pairing between the snRNAs and their target sequences at each step in the removal of an intron. She also identified proteins that formed part of the spliceosome complex with the snRNAs. Elected to the National Academy of Sciences in 1993, Guthrie edited Guide to Yeast Genetics and Molecular Biology, an influential methods series for many years.

<span class="mw-page-title-main">Kiyoshi Nagai</span> Japanese structural biologist (1949–2019)

Kiyoshi Nagai was a Japanese structural biologist at the MRC Laboratory of Molecular Biology Cambridge, UK. He was known for his work on the mechanism of RNA splicing and structures of the spliceosome.

References

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