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What is RNA ?
Ribonucleic Acid(RNA) is the genetic information carrier in biological cells, certain viruses, and viroid-like organisms. It is a chain-like molecule composed of ribonucleotides linked together by phosphodiester bonds. Ribonucleotide molecules consist of phosphate, ribose, and a base. There are four main bases in RNA, including A (Adenine), G (Guanine), C (Cytosine), and U (Uracil), where U (Uracil) replaces T (Thymine) found in DNA. Compared to DNA, RNA exhibits a wide variety of types, smaller molecular weight, and significant variations in content. Non-coding large RNAs include ribosomal RNA and long non-coding RNA. Non-coding small RNAs include transfer RNA and non-coding small RNA, which encompass transfer RNA, ribosomal RNA, ribozymes, small molecules RNA, and more. Small molecules RNA (20-300 nt) include miRNA, siRNA, piRNA, scRNA, snRNA, snoRNA, and others.
Figure 1. Many different types of RNA. (J, M, Sasso.; et al, 2022)
With the successful development of mRNA-based COVID-19 vaccines and the approval of various RNA-based novel drugs, RNA has surged to the forefront of pharmaceutical research. Apart from its role in generating antigens or therapeutic proteins, different types of RNA have various functions and play essential regulatory roles in cells and tissues. These RNAs hold potential as new therapies. In cells, mRNA can be translated to produce therapeutic proteins to replace defective or missing proteins. mRNA can also serve as therapeutic targets for antisense oligonucleotides (ASO), siRNA, miRNA, aptamers, and inhibitory tRNAs.
Classifications of RNA
Messenger RNA(mRNA)
Information is transmitted from DNA to the ribosomes in the cell (the site of protein synthesis) through RNA. The mRNA encodes the sequence that determines the amino acid sequence in the produced protein. The ribosomes translate the genetic information encoded in the messenger RNA into a protein. The folded structure in the mRNA coding region represents a kinetic barrier that reduces the rate of peptide elongation, as the ribosome must disrupt the structures it encounters in the mRNA at the entry site to allow translocation to the next codon. Cells use these structures to create various translation control strategies, such as programmed ribosomal frameshifting, regulation of protein expression levels, ribosome positioning, and co-translational protein folding.
Small Interfering RNA (siRNA)
siRNA is a double-stranded RNA molecule consisting of 20 to 25 nucleotides in length. Currently, siRNA is primarily involved in the phenomenon of RNA interference (RNAi), regulating gene expression in a highly specific manner. Additionally, siRNA also participates in some RNAi-related pathways, such as antiviral mechanisms or chromatin structure alterations. SiRNA can be introduced into cells through various transfection techniques and exerts a highly specific gene silencing effect on particular genes. Essentially, almost any known gene sequence can serve as the target for appropriately designed siRNA with complementary sequences, making siRNA a crucial tool for studying gene function and drug targets.
Transfer RNA (tRNA)
tRNA is a critical intermediary molecule in the process of protein synthesis, as it deciphers the genetic code during mRNA translation and transfers specific amino acids to the growing polypeptide chain at the ribosomal site of protein synthesis. In contrast to the traditional view of tRNA as a universally expressed housekeeping molecule, it is now increasingly recognized that tRNA-encoding genes display tissue-specific and cell-type-specific expression patterns, and both tRNA gene expression and function are dynamically regulated by post-transcriptional RNA modifications. Furthermore, tRNA dysregulation mediated by changes in tRNA abundance or function can have detrimental consequences, leading to several different human diseases, including neurological disorders and cancer. There is growing evidence that reprogramming mRNA translation by altering tRNA activity can drive pathological processes in a codon-dependent manner.
MicroRNA (miRNA)
miRNA is a class of short non-coding RNA molecules ranging in size from 19 to 25 nucleotides. They are endogenous small RNAs that regulate post-transcriptional gene expression. They serve as potent regulators of various cellular processes, influencing cell growth, differentiation, development, and apoptosis by recognizing homologous sequences and interfering with transcription, translation, or epigenetic processes. Each miRNA can target multiple genes, and several miRNAs can collectively regulate a single gene. This intricate regulatory network can control the expression of multiple genes through a single miRNA or precisely modulate the expression of a specific gene through a combination of several miRNAs. It is estimated that miRNAs regulate approximately one-third of human genes. Research suggests that about 70% of mammalian miRNAs are located in the transcribed regions, and the majority of them are found within introns. The positions of some intronic miRNAs are highly conserved across different species. The high conservation of miRNAs in both their genomic locations and sequences is closely related to their functional importance.
Long Non-Coding RNA (lncRNA)
lncRNA is a class of RNA transcripts that are longer than 200 nucleotides and do not encode proteins. Approximately 93% of transcripts are lncRNAs, and they are typically located in the cell nucleus and cytoplasm. However, the gene transcription levels of lncRNAs are generally lower than those of protein-coding genes, and their sequence conservation is poor, with less evolutionary pressure, although their promoter sequences are typically more conserved. Compared to small RNAs, lncRNAs have longer sequences and more complex spatial structures, and they participate in a wider variety of complex and diverse mechanisms in gene expression regulation. As important regulatory factors in the human genome, the functions of lncRNAs depend on their subcellular localization and interactions with other molecules. In the cell nucleus, lncRNAs regulate gene expression at the epigenetic, transcriptional, and post-transcriptional levels. In the cell cytoplasm, lncRNAs control gene expression at the translational or post-translational level. They participate in various crucial regulatory processes such as development, differentiation, metabolism, X chromosome inactivation, genomic imprinting, chromatin modification, transcriptional activation and repression, nuclear transport, and more, all of which are closely associated with the occurrence, development, and treatment of human diseases.
Ribosomal RNA (rRNA)
Although RNA serves many regulatory roles in eukaryotes, archaea, and bacteria, rRNA is the most abundant cellular RNA, surpassing almost all other functional RNAs in size. rRNA is the largest and most abundant RNA in bacterial and archaeal cells. Additionally, ribosomes consist of more than 50 ribosomal proteins (r-proteins), most of which directly interact with rRNA, forming specific interactions with RNA. Since most regulatory RNAs in bacteria seem to be relatively recent discoveries, they have certainly evolved in the context of abundant rRNA and r-proteins, and thus have been shaped by them. Many regulatory RNA structures contain portions that are very similar to sequences within rRNA. Some of this similarity arises from the role that rRNA plays in our understanding of RNA structure, while in other cases, it is due to interactions with r-proteins.
Small Nuclear RNA (snRNA)
snRNA is an essential component of the spliceosome, which catalyzes the splicing of pre-mRNA. Each snRNA forms complexes with numerous proteins, creating ribonucleoprotein complexes in the cell nucleus known as small nuclear ribonucleoproteins (snRNPs). snRNPs participate in pre-mRNA splicing by recognizing critical sequence elements present in introns, thereby forming an active spliceosome. Recognition is primarily achieved through base-pairing interactions (or nucleotide-nucleotide contacts) between snRNA and pre-mRNA. It's worth noting that snRNA undergoes extensive RNA modifications, imparting unique properties to the RNA.
Reference
- J, M, Sasso.; et al. The Progress and Promise of RNA Medicine-An Arsenal of Targeted Treatments. J. Med. Chem. 2022, 65(10): 6975-7015.
* Only for research. Not suitable for any diagnostic or therapeutic use.
