Alternative titles; symbols
HGNC Approved Gene Symbol: SNRNP70
Cytogenetic location: 19q13.33 Genomic coordinates (GRCh38): 19:49,085,451-49,108,604 (from NCBI)
The series of reactions leading to the removal of intervening sequences from pre-mRNAs to yield mature mRNA occurs in a complex known as the spliceosome. The spliceosome contains several small nuclear ribonucleoprotein complexes (snRNPs). One of these, the U1 snRNP, contains at least 3 specific proteins. Spritz et al. (1987) isolated a cDNA corresponding to the largest U1-snRNP protein, which they referred to as U1-70K. They suggested that the actual size is probably 52 kD. The protein contains 3 regions similar to known nucleic acid-binding proteins, and bound RNA in an in vitro assay. Multiple forms due to alternative splicing may exist, possibly with different functions in vivo. The human U1-70K snRNP protein is the major antigen recognized by anti-(U1)RNP sera from patients with autoimmune diseases.
Montzka and Steitz (1988) demonstrated additional complexity of the human snRNPs and stated that there are at least 12 snRNPs.
Du and Rosbash (2002) demonstrated that U1 snRNP lacking the 5-prime end of its snRNA retains 5-prime splice site sequence specificity. They also showed that recombinant yeast U1C protein, a U1 snRNP protein, selects a 5-prime splice site-like sequence in which the first 4 nucleotides, GUAU, are identical to the first 4 nucleotides of the yeast 5-prime splice site consensus sequence. Du and Rosbash (2002) proposed that a U1C 5-prime splice site interaction precedes pre-mRNA/U1 snRNA base pairing and is the earliest step in the splicing pathway.
Kaida et al. (2010) used antisense morpholino oligonucleotide to U1 snRNA to achieve functional U1 snRNP knockdown in HeLa cells, and identified accumulated unspliced pre-mRNAs by genomic tiling microarrays. In addition to inhibiting splicing, U1 snRNP knockdown caused premature cleavage and polyadenylation in numerous pre-mRNAs at cryptic polyadenylation signals, frequently in introns near (less than 5 kb) the start of the transcript. This did not occur when splicing was inhibited with U2 snRNA (180690) antisense morpholino oligonucleotide or the U2-snRNP-inactivating drug spliceostatin A unless U1 antisense morpholino oligonucleotide was also included. Kaida et al. (2010) further showed that U1 snRNA-pre-mRNA basepairing was required to suppress premature cleavage and polyadenylation from nearby cryptic polyadenylation signals located in introns. Kaida et al. (2010) concluded that their findings revealed a critical splicing-independent function for U1 snRNP in protecting the transcriptome, which they proposed explains its overabundance, with an estimated copy number of 10(6) molecules per human cell.
Using a random, mutagenesis-coupled, high-throughput method termed 'RNA elements for subcellular localization by sequencing' (mutREL-seq) in mouse and human cells, Yin et al. (2020) identified an RNA motif that recognized U1 snRNP and was essential for localization of reporter RNAs to chromatin. Across the genome, chromatin-bound long noncoding RNAs (lncRNAs) were enriched with 5-prime splice sites and depleted of 3-prime splice sites and exhibited high levels of U1 snRNA binding compared with cytoplasm-localized mRNAs. Acute depletion of U1 snRNA or of the U1 snRNP component SNRNP70 markedly reduced chromatin association of hundreds of lncRNAs and unstable transcripts without altering the overall transcription rate in cells. Rapid degradation of SNRNP70 reduced localization of both nascent and polyadenylated lncRNA transcripts to chromatin and disrupted nuclear and genomewide localization of the lncRNA Malat1 (607924). Moreover, U1 snRNP interacted with transcriptionally engaged RNA polymerase II (see 180660). The authors concluded that U1 snRNP acts widely to tether and mobilize lncRNAs to chromatin in a transcription-dependent manner.
Spritz et al. (1990) reported that the SNRP70 gene is greater than 44 kb, with 11 exons. Nelissen et al. (1991) concluded that the SNRP70 gene is present in single copy, consists of 6 exons, and is 14 to 16 kb long.
Crystal Structure
An electron density map of the functional core of U1 snRNP at 5.5-angstrom resolution enabled Pomeranz Krummel et al. (2009) to build the RNA and, in conjunction with site-specific labeling of individual proteins, to place the 7 Sm proteins, SNRPD1 (601063); SNRPD2 (601061); SNRPD3 (601062); SNRPF (603541); SNRPE (128260); SNRPG (603542); and SNRPB (182282) as well as U1C (SNRPC; 603522) and U170K into the map. Pomeranz Krummel et al. (2009) presented the detailed structure of the spliceosomal snRNP, revealing a hierarchical network of intricate interactions between subunits. A striking feature is the amino-terminal polypeptide of U170K, which extends over a distance of 80 angstroms from its RNA binding domain, wraps around the core domain consisting of the 7 Sm proteins, and finally contacts U1C, which is crucial for 5-prime-splice-site recognition. Pomeranz Krummel et al. (2009) concluded that the structure of U1 snRNP provides insights into U1 snRNP assembly and suggests a possible mechanism of 5-prime-splice-site recognition.
Cryoelectron Microscopy
Charenton et al. (2019) reported cryoelectron microscopy structures of the human pre-B spliceosome complex captured before U1 snRNP dissociation at 3.3-angstrom core resolution and the human U4/U6.U5 tri-snRNP at 2.9-angstrom resolution. U1 snRNP inserts the 5-prime splice site-U1 snRNA helix between the 2 RecA domains of the Prp28 DEAD-box helicase (DDX23; 612172). ATP-dependent closure of the Prp28 RecA domains releases the 5-prime splice site to pair with the nearby U6 ACAGAGA-box sequence presented as a mobile loop. The structures suggested that formation of the 5-prime splice site-ACAGAGA helix triggers remodeling of an intricate protein-RNA network to induce Brr2 helicase relocation to its loading sequence in U4 snRNA, enabling Brr2 to unwind the U4/U6 snRNA duplex to allow U6 snRNA to form the catalytic center of the spliceosome.
By use of the cDNA clone and the study of somatic cell hybrids, Barton et al. (1987) demonstrated that the gene encoding this protein is located on chromosome 19. See also Spritz et al. (1987).
Spritz et al. (1990) mapped the SNRP70 gene to 19q13.3 by a combination of Southern analysis of DNAs from somatic cell hybrids and in situ hybridization. Nelissen et al. (1991) likewise mapped the gene to 19q.
Barton, D. E., Spritz, R. A., Francke, U. RPU1 encoding the 68kDa U1 snRNP-associated protein is located on chromosome 19. (Abstract) Cytogenet. Cell Genet. 46: 577 only, 1987.
Charenton, C., Wilkinson, M. E., Nagai, K. Mechanism of 5-prime splice site transfer for human spliceosome activation. Science 364: 362-367, 2019. [PubMed: 30975767] [Full Text: https://doi.org/10.1126/science.aax3289]
Du, H., Rosbash, M. The U1 snRNP protein U1C recognizes the 5-prime splice site in the absence of base pairing. Nature 419: 86-90, 2002. [PubMed: 12214237] [Full Text: https://doi.org/10.1038/nature00947]
Kaida, D., Berg, M. G., Younis, I., Kasim, M., Singh, L. N., Wan, L., Dreyfuss, G. U1 snRNP protects pre-mRNAs from premature cleavage and polyadenylation. Nature 468: 664-668, 2010. [PubMed: 20881964] [Full Text: https://doi.org/10.1038/nature09479]
Montzka, K. A., Steitz, J. A. Additional low-abundance human small nuclear ribonucleoproteins: U11, U12, etc. Proc. Nat. Acad. Sci. 85: 8885-8889, 1988. [PubMed: 2973606] [Full Text: https://doi.org/10.1073/pnas.85.23.8885]
Nelissen, R. L., Sillekens, P. T., Beijer, R. P., Geurts van Kessel, A. H., van Venrooij, W. J. Structure, chromosomal localization and evolutionary conservation of the gene encoding human U1 snRNP-specific A protein. Gene 102: 189-196, 1991. [PubMed: 1831431] [Full Text: https://doi.org/10.1016/0378-1119(91)90077-o]
Pomeranz Krummel, D. A., Oubridge, C., Leung, A. K. W., Li, J., Nagai, K. Crystal structure of human spliceosomal U1 snRNP at 5.5-angstrom resolution. Nature 458: 475-480, 2009. [PubMed: 19325628] [Full Text: https://doi.org/10.1038/nature07851]
Spritz, R. A., Strunk, K., Surowy, C. S., Hoch, S. O., Barton, D. E., Francke, U. Human U1-70K snRNP protein: cDNA cloning, chromosomal localization, expression, alternative splicing and RNA-binding. Nucleic Acids Res. 15: 10373-10391, 1987. [PubMed: 2447561] [Full Text: https://doi.org/10.1093/nar/15.24.10373]
Spritz, R. A., Strunk, K., Surowy, C. S., Mohrenweiser, H. W. Human U1-70K ribonucleoprotein antigen gene: organization, nucleotide sequence, and mapping to locus 19q13.3. Genomics 8: 371-379, 1990. [PubMed: 2147422] [Full Text: https://doi.org/10.1016/0888-7543(90)90295-6]
Yin, Y., Lu, J. Y., Zhang, X., Shao, W., Xu, Y., Li, P., Hong, Y., Cui, L., Shan, G., Tian, B., Zhang, Q. C., Shen, X. U1 snRNP regulates chromatin retention of noncoding RNAs. Nature 580: 147-150, 2020. [PubMed: 32238924] [Full Text: https://doi.org/10.1038/s41586-020-2105-3]