Small nuclear RNAs (snRNAs) are a distinct class of RNA molecules found within the nucleus of eukaryotic cells. These molecules are relatively small in size compared to other RNA types and play a fundamental role in various cellular processes. Unlike messenger RNA (mRNA) that carries genetic information for protein synthesis, snRNAs are non-coding RNAs, meaning they do not directly translate into proteins. Instead, they perform regulatory and catalytic functions within the cell.
What are Small Nuclear RNAs?
Small nuclear RNAs typically range from 60 to 300 nucleotides. They are exclusively located within the cell’s nucleus, residing in specific regions like splicing speckles and Cajal bodies. SnRNAs do not exist in isolation; they consistently associate with specific proteins to form complexes known as small nuclear ribonucleoproteins (snRNPs). Each snRNP complex comprises an snRNA component and several snRNP-specific proteins, including the Sm proteins.
There are several distinct types of snRNAs, with the most common human varieties being U1, U2, U4, U5, and U6. Their names often begin with “U” due to their high uridine content. These molecules are transcribed by either RNA polymerase II or RNA polymerase III, depending on the specific snRNA class.
Small Nuclear RNAs in Gene Splicing
A primary function of snRNAs is their involvement in gene splicing. After a gene is transcribed from DNA into a precursor messenger RNA (pre-mRNA) molecule, this pre-mRNA contains coding regions (exons) and non-coding regions (introns). Gene splicing is the process where these introns are removed, and the remaining exons are joined to form a mature messenger RNA (mRNA) molecule, which carries instructions for protein synthesis.
This editing is carried out by a large molecular machine known as the spliceosome. The spliceosome is assembled from five core snRNAs (U1, U2, U4, U5, and U6) and over 150 associated proteins. The process begins with U1 snRNP recognizing the 5′ splice site of an intron, while U2 snRNP binds to a specific branch point within the intron. The U4/U6-U5 tri-snRNP complex then joins the assembly.
This leads to conformational changes, including unwinding of U4 and U6 snRNAs, and release of U1 and U4 snRNPs. The activated spliceosome (containing U2, U5, and U6 snRNPs) then catalyzes two transesterification reactions. This results in the excision of the intron, often forming a lariat structure, and the ligation of the flanking exons, ensuring that only the correct coding sequences are present in the final mRNA.
Other Roles of Small Nuclear RNAs
Beyond gene splicing, snRNAs also participate in other cellular processes. One function involves the processing of histone messenger RNA (mRNA) precursors. Unlike most mRNA molecules, histone mRNAs do not undergo polyadenylation (the addition of a poly-A tail) at their 3′ end. Instead, U7 snRNA, with its associated proteins (U7 snRNP), directly regulates the cleavage and formation of the 3′ end of replication-dependent histone mRNAs. This processing is sensitive to the cell cycle, with U7 snRNA becoming more accessible during the S phase when histone synthesis peaks.
Another role for some snRNAs, specifically telomeric repeat-containing RNAs (TERRA), is maintaining telomeres. Telomeres are protective caps at chromosome ends that safeguard genetic information during cell division. TERRA transcripts contribute to regulating telomere function and stability, influencing DNA replication and DNA damage response. SnRNAs also influence RNA biogenesis, including transcriptional regulation and RNA stability, by coordinating different RNA processing events.
Small Nuclear RNAs and Human Health
Dysfunction in small nuclear RNAs can impact human health, as errors in RNA processing can lead to incorrect or non-functional proteins. Abnormalities in snRNA function or spliceosome assembly are linked to various diseases. For instance, spinal muscular atrophy (SMA), a severe motor neuron degenerative disease, is caused by insufficient levels of the survival motor neuron (SMN) protein. The SMN protein is essential for the assembly of spliceosomal snRNPs. A reduction in SMN levels leads to defects in snRNP biogenesis, impacting pre-mRNA splicing fidelity.
Defects in snRNAs or spliceosome components are also linked to certain cancers. Alterations in the expression or function of specific snRNAs can disrupt normal gene expression patterns, contributing to uncontrolled cell growth and proliferation. For example, variants in the RNU4-2 gene (which encodes the U4 snRNA) have been identified as a cause of neurodevelopmental disorders like ReNU syndrome, highlighting the link between snRNA integrity and human disease. Understanding the roles of snRNAs in health and disease could open new avenues for developing diagnostic tools and therapeutic strategies.