U1 snRNP is an RNA splicing molecule involved in maturing mRNA. It comprises of small nuclear RNA (U1 RNA) and proteins. U1 snRNP attaches to other snRNPs, raw pre-mRNA, and proteins. Splicing is one of those kinds of post-transcriptional editing that is a nucleus edit. U1 snRNP (small nuclear ribonucleoprotein) belongs to the RNA processing apparatus, and is associated with systemic lupus erythematosus, mixed connective tissue disease, rheumatoid arthritis and amyotrophic lateral sclerosis. This connection between U1 snRNP activity and brain health creates even more possibilities for studying and treating neurodegenerative disease.
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U1 snRNP Biosynthesis
U1 snRNP is a giant splicing factor made up of small nuclear RNA (snRNA) and proteins. RNA polymerase II copies U1 snRNA into the nucleus of the cell. U1 snRNA after transcription is spliced, capped, and polyadenylated into mature U1 snRNA. Then the U1 snRNA gets carried back and forth between the nucleus and the cytoplasm, binding to proteins to create the U1 snRNP complex. U1 snRNP assembly is in the nucleus. U1 snRNA gets attached to one end of the nucleosome and then other proteins attach themselves to make the U1 snRNP complex. Such proteins are U1-A, U1-C, Sm, and so on. The U1 snRNP, assembled as a package, helps pre-mRNA splice because it targets the pre-mRNA 5′ splice site to recognize the splicing site.
Fig. 1 U1 snRNP Pathway of Biosynthesis (Campagne, S et al., 2024).
Structure and Function of U1 snRNP
The U1 spliceosomal RNA of human genes is 164 base pairs long, contains four stem loops, and is capped at the 5' end with 5'-trimethylguanosine. Bases 3–10 are nested segments that base-pair to the 5' end of the intron in RNA splicing, and bases 126–133 are the Sm site around which the Sm loop is structured. U1 small nuclear ribonucleoprotein (snRNP): contains U1 snRNA, a heptameric Sm protein ring, and three U1 proteins (U1-A, U1-C, and U1-70K). U1 snRNP crystal structure (Three-dimensional crystal structure) shows its detailed design. U1 snRNP serves as a seed particle, playing a crucial role in the spliceosome assembly process by binding to and positioning the 5' splice site, achieved by introducing the 5' end of U1 snRNA into the 5' splice site. The main activities and properties of U1 snRNP are as follows:
Splicing Mechanism
This is primarily because U1 snRNP specifically recognizes the 5' splice site of pre-mRNA. It binds to the consensus sequence at the beginning of introns and facilitates the removal of introns while joining exons together.
Interactions
U1 snRNP is a part of the spliceosome, a giant molecular unit used to splice pre-mRNA. Along with U1, there are other snRNPs (U2, U4, U5, U6), proteins, and other things that act as a part of this complex.
Alternative Splicing
U1 snRNP plays a crucial role in alternative splicing, a process in which various combinations of exons are joined to produce multiple mRNA variants from a single gene. The splicing machinery responsible for mRNA splicing, as well as other functions related to transcription, mRNA stability, and alternative splicing, is significantly influenced by U1 snRNP. These activities position U1 snRNP at the forefront of the regulatory landscape of gene expression.
U1 snRNP Complex Assembly
>U1 snRNP is an omnipresent RNP complex that removes introns from pre-mRNA. U1 snRNP comprises U1-snRNA, seven primary Sm proteins, and three U1 proteins (U1-70K, U1-A, and U1-C) U1 snRNP drives spliceosome assembly on pre-mRNA by binding to the 5′ splice site and ATP-dependent recruiting of U2 snRNP to the branch for cleavage. SR proteins are also the only ones that allow U1 snRNP to interact with other 5′ splice sites and control alternative splicing. The immune mechanism of U1 snRNP immunogenicity is epitope diffusion through B- and T-cell interactions, apoptotic responses, and U1-snRNA-induced stimulation of Toll-like receptors (TLRs).
Role of U1 snRNP in Disease
U1 snRNP (small nuclear ribonucleoprotein) is involved in RNA processing and has been associated with various disorders, particularly those related to protein misfolding.
Rheumatic Autoimmune Diseases
That's the structural feature that makes self-antigen complexes susceptible to autoimmune attacks. Autoreactive B and T cells detect the U1 small nuclear ribonucleoprotein particles (snRNPs) in various rheumatic diseases including systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD).
Familial Amyotrophic Lateral Sclerosis (ALS)
The major components of U1 snRNP, specifically the Sm protein and U1 snRNA, are both mislocalized to the cytoplasm. Additionally, a mutant form of a protein called FUS is also mislocalized; ideally, FUS should reside in the nucleus due to its exposed nuclear localization sequence.
Conclusion
U1 snRNP is an RNA splicing complex, which is a common eukaryotic RNP complex that we think is what eliminates introns from pre-mRNA. U1 snRNP's elements are transcribed with fine regulation, critical for homeostasis. U1 RNA is manufactured and proteins are assembled precisely so that there is always a functional U1 snRNP complex. As a functional complex, U1 RNA and some proteins form a 'splice-spotting' marker. The more we can piece together what happens inside U1 snRNP, the better drugs we'll be able to build, and the better we'll learn about molecular modulators of gene expression in both health and disease.
References
- Nagai, K.; et al. Structure and assembly of the spliceosomal snRNPs.15-26. Biochem Soc Trans 2001, 29 (2): 15-26.
- Campagne, S.; et al. U1 snRNP Biogenesis Defects in Neurodegenerative Diseases. ChemBioChem 2024, 25(9): e202300864.
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