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U1 spliceosomal RNA

December 18, 2023

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.

U1 spliceosomal RNA
Identifiers
SymbolU1
RfamRF00003
Other data
RNA typeGene; snRNA; splicing
Domain(s)Eukaryota
GOGO:0000368 GO:0030627 GO:0005685
SOSO:0000391
PDB structuresPDBe

Structure and function edit

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 edit

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 edit

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 edit

References edit

  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 edit

  • Oubridge C, Ito N, Evans PR, Teo CH, Nagai K (December 1994). "Crystal structure at 1.92 A resolution of the RNA-binding domain of the U1A spliceosomal protein complexed with an RNA hairpin". Nature. 372 (6505): 432–8. Bibcode:1994Natur.372..432O. doi:10.1038/372432a0. PMID 7984237. S2CID 9404488.
  • Katsamba PS, Myszka DG, Laird-Offringa IA (June 2001). "Two functionally distinct steps mediate high affinity binding of U1A protein to U1 hairpin II RNA". The Journal of Biological Chemistry. 276 (24): 21476–81. doi:10.1074/jbc.M101624200. PMID 11297556.

External links edit

  • Page for U1 spliceosomal RNA at Rfam

December 18, 2023
spliceosomal, small, nuclear, snrna, component, snrnp, small, nuclear, ribonucleoprotein, protein, complex, that, combines, with, other, snrnps, unmodified, mrna, various, other, proteins, assemble, spliceosome, large, protein, molecular, complex, upon, which,. 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 U1 spliceosomal RNAPredicted secondary structure and sequence conservation of U1IdentifiersSymbolU1RfamRF00003Other dataRNA typeGene snRNA splicingDomain s EukaryotaGOGO 0000368 GO 0030627 GO 0005685SOSO 0000391PDB structuresPDBe Contents 1 Structure and function 2 Role in Disease 3 Role in Genome wide Telescripting 4 See also 5 References 6 Further reading 7 External linksStructure and function editIn 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 editU1 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 editTelescripting 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 editMicroRNA Small nuclear RNA U2 spliceosomal RNAReferences edit 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 Stark H Dube P Luhrmann 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 Weaver RF 2005 Molecular Biology Boston McGraw Hill pp 433 ISBN 9780072846119 OCLC 53900694 Will CL Luhrmann 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 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 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 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 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 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 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 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 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 amp Molecular Biology 24 11 993 999 doi 10 1038 nsmb 3473 PMC 5685549 PMID 28967884 Further reading editOubridge C Ito N Evans PR Teo CH Nagai K December 1994 Crystal structure at 1 92 A resolution of the RNA binding domain of the U1A spliceosomal protein complexed with an RNA hairpin Nature 372 6505 432 8 Bibcode 1994Natur 372 432O doi 10 1038 372432a0 PMID 7984237 S2CID 9404488 Katsamba PS Myszka DG Laird Offringa IA June 2001 Two functionally distinct steps mediate high affinity binding of U1A protein to U1 hairpin II RNA The Journal of Biological Chemistry 276 24 21476 81 doi 10 1074 jbc M101624200 PMID 11297556 External links editPage for U1 spliceosomal RNA at Rfam Retrieved from https en wikipedia org w index php title U1 spliceosomal RNA amp oldid 1186731707, wikipedia, wiki, book, books, library,

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