U1 spliceosomal RNA

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U1 spliceosomal RNA
RF00003-rscape.svg
Predicted secondary structure and sequence conservation of U1
Identifiers
SymbolU1
Rfam RF00003
Other data
RNA type Gene; snRNA; splicing
Domain(s) Eukaryota
GO GO:0000368 GO:0030627 GO:0005685
SO SO:0000391
PDB structures PDBe

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 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.

Contents

Structure and function

In humans, the U1 spliceosomal RNA is 164 bases long, forms four stem-loops, and possesses a 5'-trimethylguanosine five-prime cap. Bases 3 to 10 are a conserved sequence that base-pairs with the 5' splice site of introns during RNA splicing, and bases 126 to 133 form the Sm site, around which the Sm ring is assembled. Stem-loop I binds to the U1-70K protein, stem-loop II binds to the U1 A protein, stem-loops III and IV bind to the core RNP domain, a heteroheptameric Sm ring consisting of SmB/B', SmD1/2/3, SmE, SmF, and SmG. U1 C interacts primarily through protein-protein interactions. [1] [2]

Experimentation has demonstrated that the binding of U1 snRNA to the 5'-splice site is necessary, but not sufficient, to begin spliceosome assembly. [3] Following recruitment of the U2 snRNP and U5.U4/U6 tri-snRNP the spliceosome transfers the 5'-splice site from the U1 snRNA to U6 snRNA before splicing catalysis occurs. [4]

There are significant differences in sequence and secondary structure between metazoan and yeast U1 snRNAs, the latter being much longer (568 nucleotides as compared to 164 nucleotides in humans). Nevertheless, secondary structure predictions suggest that all U1 snRNAs share a 'common core' consisting of helices I, II, the proximal region of III, and IV. [5] This family does not contain the larger yeast sequences.

A non-canonical role for U1 snRNP has recently been described in the regulation of alternative polyA site selection [6] It is proposed that increased transcription rates "sponge" U1 snRNP, decreasing its availability. This model is supported experimentally, as reducing U1 snRNP levels with antisense morpholino oligonucleotides led to a dose-dependent shift of polyA usage to generate shorter mRNA transcripts.

Role in Disease

U1 snRNP has been implicated in many diseases, especially in those characterized by the presence of misfolded proteins. For instance, a protein component of U1 snRNP called U1-70k from the brain cells of healthy individuals was found to become insoluble in the presence of amyloid aggregates from the brain cells of patients with Alzheimer's disease. [7] [8] U1 overexpression elevates the expression level of autophagy and alters lysosomal biogenesis [9]

Similarly in fibroblast cells of patients with a familial form of amyotrophic lateral sclerosis (ALS), the core components of U1 snRNP (namely, the Sm proteins and U1 snRNA) were found to co-mislocalize to the cytoplasm with the mutant version of a protein called FUS (ideally, FUS should localize to the nucleus since it possesses an exposed nuclear localization sequence). The authors of this study also found that experimentally knocking down U1 snRNP, lead to truncations in the axons of motor neurons, suggesting that splicing defects might have a role to play in ALS pathogenesis. [10]

Role in Genome-wide Telescripting

Telescripting is a process by which U1 snRNP suppresses premature cleavage and polyadenylation (PCPA) and allows large transcripts to be synthesized when needed in the cell. Introns possess what are called polyadenylation signals (PAS). These sites are where pre-mRNA can get terminated by cleavage and polyadenylation (a process termed PCPA). [11] In addition to its role in 5' splice site recognition, U1 snRNP protects nascent transcripts by sheltering these exposed PAS in the pre-mRNA such that elongation can continue. Moreover, it has been found that U1 telescripting is particularly important for long-distance transcription elongation in introns of large genes that have a median size of 39 kilo base pairs. [12]

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.

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. 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 or RNA polymerase II, and maintaining the telomeres.

Gideon Dreyfuss is an American biochemist, the Isaac Norris Professor of Biochemistry and Biophysics at the University of Pennsylvania School of Medicine, and an investigator of the Howard Hughes Medical Institute. He was elected to the National Academy of Sciences in 2012.

<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">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">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.

snRNP70 Protein-coding gene in the species Homo sapiens

snRNP70 also known as U1 small nuclear ribonucleoprotein 70 kDa is a protein that in humans is encoded by the SNRNP70 gene. snRNP70 is a small nuclear ribonucleoprotein that associates with U1 spliceosomal RNA, forming the U1snRNP a core component of the spliceosome. The U1-70K protein and other components of the spliceosome complex form detergent-insoluble aggregates in both sporadic and familial human cases of Alzheimer's disease. U1-70K co-localizes with Tau in neurofibrillary tangles in Alzheimer's disease.

<span class="mw-page-title-main">Small nuclear ribonucleoprotein D1</span> Protein-coding gene in the species Homo sapiens

Small nuclear ribonucleoprotein Sm D1 is a protein that in humans is encoded by the SNRPD1 gene.

<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">Small nuclear ribonucleoprotein polypeptide E</span> Protein-coding gene in the species Homo sapiens

Small nuclear ribonucleoprotein E is a protein that in humans is encoded by the SNRPE gene.

<span class="mw-page-title-main">SNRPD3</span> Protein-coding gene in the species Homo sapiens

Small nuclear ribonucleoprotein Sm D3 is a protein that in humans is encoded by the SNRPD3 gene.

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

Small nuclear ribonucleoprotein F is a protein that in humans is encoded by the SNRPF gene.

<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">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

  1. ↑ Nagai K, Muto Y, Pomeranz Krummel DA, Kambach C, Ignjatovic T, Walke S, Kuglstatter A (May 2001). "Structure and assembly of the spliceosomal snRNPs. Novartis Medal Lecture". Biochemical Society Transactions. 29 (Pt 2): 15–26. doi:10.1042/bst0290015. PMID   11356120.
  2. ↑ Stark H, Dube P, Lührmann R, Kastner B (January 2001). "Arrangement of RNA and proteins in the spliceosomal U1 small nuclear ribonucleoprotein particle". Nature. 409 (6819): 539–42. Bibcode:2001Natur.409..539S. doi:10.1038/35054102. PMID   11206553. S2CID   4421636.
  3. ↑ Weaver RF (2005). Molecular Biology . Boston: McGraw-Hill. pp.  433. ISBN   9780072846119. OCLC   53900694.
  4. ↑ Will CL, Lührmann R (July 2011). "Spliceosome structure and function". Cold Spring Harbor Perspectives in Biology. 3 (7): a003707. doi:10.1101/cshperspect.a003707. PMC   3119917 . PMID   21441581.
  5. ↑ Zwieb C (January 1997). "The uRNA database". Nucleic Acids Research. 25 (1): 102–3. doi:10.1093/nar/25.1.102. PMC   146409 . PMID   9016512.
  6. ↑ Berg MG, Singh LN, Younis I, Liu Q, Pinto AM, Kaida D, Zhang Z, Cho S, Sherrill-Mix S, Wan L, Dreyfuss G (July 2012). "U1 snRNP determines mRNA length and regulates isoform expression". Cell. 150 (1): 53–64. doi:10.1016/j.cell.2012.05.029. PMC   3412174 . PMID   22770214.
  7. ↑ Diner I, Hales CM, Bishof I, Rabenold L, Duong DM, Yi H, Laur O, Gearing M, Troncoso J, Thambisetty M, Lah JJ, Levey AI, Seyfried NT (December 2014). "Aggregation properties of the small nuclear ribonucleoprotein U1-70K in Alzheimer disease". The Journal of Biological Chemistry. 289 (51): 35296–313. doi: 10.1074/jbc.M114.562959 . PMC   4271217 . PMID   25355317.
  8. ↑ Bai B, Hales CM, Chen PC, Gozal Y, Dammer EB, Fritz JJ, Wang X, Xia Q, Duong DM, Street C, Cantero G, Cheng D, Jones DR, Wu Z, Li Y, Diner I, Heilman CJ, Rees HD, Wu H, Lin L, Szulwach KE, Gearing M, Mufson EJ, Bennett DA, Montine TJ, Seyfried NT, Wingo TS, Sun YE, Jin P, Hanfelt J, Willcock DM, Levey A, Lah JJ, Peng J (October 2013). "U1 small nuclear ribonucleoprotein complex and RNA splicing alterations in Alzheimer's disease". Proceedings of the National Academy of Sciences of the United States of America. 110 (41): 16562–7. Bibcode:2013PNAS..11016562B. doi: 10.1073/pnas.1310249110 . PMC   3799305 . PMID   24023061.
  9. ↑ Cheng Z, Du Z, Zhai B, Yang Z, Zhang T (January 2018). "U1 small nuclear RNA overexpression implicates autophagic-lysosomal system associated with AD". Neuroscience Research. 136: 48–55. doi:10.1016/j.neures.2018.01.006. PMID   29395359. S2CID   19262444.
  10. ↑ Yu Y, Chi B, Xia W, Gangopadhyay J, Yamazaki T, Winkelbauer-Hurt ME, Yin S, Eliasse Y, Adams E, Shaw CE, Reed R (March 2015). "U1 snRNP is mislocalized in ALS patient fibroblasts bearing NLS mutations in FUS and is required for motor neuron outgrowth in zebrafish". Nucleic Acids Research. 43 (6): 3208–18. doi:10.1093/nar/gkv157. PMC   4381066 . PMID   25735748.
  11. ↑ Berg MG, Singh LN, Younis I, Liu Q, Pinto AM, Kaida D, Zhang Z, Cho S, Sherrill-Mix S, Wan L, Dreyfuss G (July 2012). "U1 snRNP determines mRNA length and regulates isoform expression". Cell. 150 (1): 53–64. doi:10.1016/j.cell.2012.05.029. PMC   3412174 . PMID   22770214.
  12. ↑ Oh JM, Di C, Venters CC, Guo J, Arai C, So BR, Pinto AM, Zhang Z, Wan L, Younis I, Dreyfuss G (November 2017). "U1 snRNP telescripting regulates a size-function-stratified human genome". Nature Structural & Molecular Biology. 24 (11): 993–999. doi:10.1038/nsmb.3473. PMC   5685549 . PMID   28967884.

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