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U1 spliceosomal RNA

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U1 spliceosomal RNA
Predicted secondary structure and sequence conservation of U1
Identifiers
SymbolU1
RfamRF00003
Other data
RNA typeGene; snRNA; splicing
Domain(s)Eukaryota
GOGO:0000368 GO:0030627 GO:0005685
SOSO:0000391
PDB structuresPDBe

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.

Structure and function

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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

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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

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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

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References

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  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.

Further reading

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