RNA

Ribonucleic acid (RNA) is one of the three major biomolecules (along with DNA and proteins) that are essential for all known forms of life.

The chemical structure of RNA is very similar to that of DNA, with two differences, (a) RNA contains the sugar ribose instead of sugar deoxyribose and (b) RNA has the nucleotide uracil in place of DNA’s thymine .

Most RNA molecules exists as single stranded and can adopt complex three-dimensional structures. RNA are biosynthesized by a process known as transcription mediated by an enzyme RNA polymerase.

RNA play essential role in many important processes like translation i.e. protein synthesis where mRNA, r RNA and tRNA play a crucial role by diligently encoding proteins for the message. They also play role in controlling gene expression, or sensing and communicating responses to cellular signals. In the absence of proteins, catalyzing enzymes, RNA can also perform biocatalysis.

Messenger RNA (mRNA)

Transfer RNA (tRNA)

Ribosomal RNA (rRNA)

Transfer-messenger RNA (tmRNA)

Heterogenous nuclear RNA (hnRNA)

Micro RNAs (miRNA)

Small interfering RNAs (siRNA)

Piwi-interacting RNAs (piRNA)

CRISPR RNAs

small nuclear RNAs (snRNA)

small nucleolar RNAs (snoRNA)

Ribozymes

Non-coding RNA

In translation

Regulatory RNAs

In RNA processing

RNAs in Translation

Messenger RNA (mRNA)

Messenger ribonucleic acid (mRNA), like DNA, carries unique codes in different series of patterns that relay messages to structures within the cell. mRNA is transcribed from a DNA template, and carries coding information to the sites of protein synthesis: the ribosomes. In mRNA as in DNA, genetic information is encoded in the sequence of nucleotides arranged into codons consisting of three bases each. Each codon encodes for a specific amino acid, except the stop codons that terminate protein synthesis. This process requires two other types of RNA: transfer RNA (tRNA) mediates recognition of the codon and provides the corresponding amino acid, while ribosomal RNA (rRNA) is the central component of the ribosome's protein manufacturing machinery.

Structure

Structure of mRNA divided into 5’ cap, untranslated region, coding region and a poly A tail.

The 5' cap is a modified guanine nucleotide added to the "front" (5' end) of the pre-mRNA using a 5'-5'-triphosphate linkage. This modification is critical for recognition and proper attachment of mRNA to the ribosome, as well as protection from 5' exonucleases. It is also important for other essential processes, such as splicing and transport.

Untranslated regions (UTRs) are sections of the mRNA before the start codon and after the stop codon that are not translated, termed the five prime untranslated region (5' UTR) and three prime untranslated region (3' UTR), respectively. These regions are transcribed with the coding region and thus are exonic as they are present in the mature mRNA. Several roles in gene expression have been attributed to the untranslated regions, including mRNA stability, mRNA localization, and translational efficiency.

Coding regions are composed of codons, which are translated into one protein in eukaryotes and in prokaryotes usually into several proteins by the ribosome. Coding regions begin with the start codon and end with a stop codon. The coding regions tend to be stabilised by internal base pairs, this impedes degradation. In addition to being protein-coding, portions of coding regions may serve as regulatory sequences in the pre-mRNA asexonic splicing enhancers or exonic splicing silencers.

The 3' poly(A) tail is a long sequence of adenine nucleotides added to the 3' end of the pre-mRNA. This tail promotes export from the nucleus and translation, and protects the mRNA from degradation.

Figure 1. showing structure of a mature eukaryotic mRNA. A fully processed mRNA includes a 5' cap, 5' UTR, coding region, 3' UTR, and poly (A) tail.

Function

Because prokaryotic mRNA does not need to be processed or transported, translation by the ribosome can begin immediately after the end of transcription. Therefore, it can be said that prokaryotic translation is coupled to transcription and occurs co-transcriptionally.Eukaryotic mRNA that has been processed and transported to the cytoplasm (i.e. mature mRNA) can then be translated by the ribosome. Translation may occur at ribosomes free-floating in the cytoplasm, or directed to the endoplasmic reticulum by the signal recognition particle. Therefore, unlike prokaryotes, eukaryotic translation is not directly coupled to transcription.

Ribosomal RNA (rRNA)

Ribosomal ribonucleic acid (rRNA) is the RNA component of the ribosome, the protein manufacturing organelle of all living cells. Ribosomal RNA provides a mechanism for decodingmRNA into amino acids and interacts with tRNAs during translation by providing peptidyl transferase activity. The tRNAs bring the necessary amino acids corresponding to the appropriate mRNA codon.

Structure

The ribosomal RNAs form two subunits, the large subunit and small subunit. mRNA is sandwiched between the small and large subunits and the ribosome catalyzes the formation of a peptide bond between the 2 amino acids that are contained in the rRNA.

Function

rRNA is the target of several clinically relevant antibiotics: chloramphenicol, erythromycin, etc. rRNA is the one of the only genes present in all cells. For this reason, genes that encode the rRNA (rDNA) are sequenced to identify an organism's taxonomic group, calculate related groups, and estimate rates of species divergence.

Transfer RNA (tRNA)

Transfer RNA (tRNA) is a small RNA molecule (usually about 73-95 nucleotides) that transfers a specific active amino acid to a growing polypeptide chain at the ribosomal site of protein synthesis during translation. They are the adaptor molecules, which form the link between the mRNA and the polypeptide that is being synthesized. Each type of tRNA molecule can be attached to only one type of amino acid, but because the genetic code contains multiple codons that specify the same amino acid, tRNA molecules bearing different anticodons may also carry the same amino acid.

Structure

The structure of tRNA can be decomposed into its primary structure, its secondary structure (usually visualized as the cloverleaf structure), and its tertiary structure (all tRNAs have a similar L-shaped 3D structure). It has a 3' terminal site for amino acid attachment. This covalent linkage is catalyzed by an aminoacyl tRNA synthetase. It also contains a three base region called the anticodon that can base pair to the corresponding three base codon region on mRNA.

The 5'-terminal phosphate group. The acceptor stem is a 7-base pair stem which contains the CCA 3'-terminal group used to attach the amino acid. The acceptor stem may contain non-Watson-Crick base pairs. The D arm is a 4 bp stem ending in a loop that often contains dihydrouridine. The anticodon arm is a 5-bp stem whose loop contains the anticodon. The T arm is a 5 bp stem containing the sequence TΨC where Ψ is a pseudouridine.

Figure 2. showing cloverleaf structure of tRNA.

Function

transfer RNA (tRNA) has role in gene expression. During gene expression, DNA is first transcribed into messenger RNA. Next, tRNA molecules—each carrying an amino acid as cargo—bind to successive nucleotides in the messenger RNA. A ribosome links these amino acids together to form a protein, and the unloaded tRNAs are subsequently released. tRNA also helps control apoptosis, or programmed cell death. tRNA also binds to cytochrome c, stopping it from binding to Apaf-1 and thereby preventing apoptosis. tRNA is highly expressed in tumor cells. It inhibits apoptosis in these cells.

Transfer-messenger RNA (tmRNA)

Transfer-messenger RNA abbreviated as tmRNA also known as 10Sa RNA and by its genetic name SsrA. It is found in bacteria, it exhibits the properties of both tRNA and messenger RNA. The tmRNA forms a ribonucleoprotein complex with Small Protein B (SmpB), Elongation Factor Tu (EF-Tu), and ribosomal protein S1.

Structure

Important feature of every tmRNA is the conserved tRNA-like domain (TLD), composed of helices 1, 12, and 2a which are analogous to the tRNA acceptor stem, T-stem and variable stem. It contains the 5' monophosphate and alanylatable 3' CCA ends. The mRNA-like region (MLR) is in standard tmRNA a large loop containing pseudoknots and a coding sequence (CDS) for the tag peptide, marked by the resume codon and the stop codon. The encoded tag peptide (ANDENYALAA in E. coli) varies among bacteria, perhaps depending on the set of proteases and adaptors available.

Figure 3. showing structure of tmRNA

Function

In trans-translation, where ribosome has stalled in the middle of protein synthesis, tmRNA and its associated proteins bind to bacterial ribosomes and recycles the stalled ribosome, adds a proteolysis-inducing tag to the unfinished polypeptide, and facilitates the degradation of the aberrant messenger RNA. In the majority of bacteria these functions are carried out by standard one-piece tmRNAs. In other bacterial species, a permuted ssrA gene produces a two-piece tmRNA in which two separate RNA chains are joined by base pairing.

Figure 4. showing trans-Translation stages A through F. A ribosome with its RNA binding sites, designated E, P, and A, is stuck near the 3' end of a broken mRNA. The tmRNP binds to the A-site, allowing the ribosome to switch templates from the broken message onto the open reading frame of the tmRNA via the resume codon (blue GCA). Regular translation eventually resumes. Upon reaching the tmRNA stop codon (red UAA), a hybrid protein with a proteolysis tag (green beads) is released.

Heterogenous nuclear RNA (hnRNA)

Heterogeneous nuclear RNA is also termed as precursor mRNA. It is immature single strand of mRNA. Pre-mRNA is produced during transcription from DNA template in cell nucleus. After processing of pre-mRNA it is called as mature mRNA or mRNA. During the processing of eukaryotic pre-mRNA exons are retained while introns are removed by spliceosomes by a process of splicing. After processing mature mRNA is exported out of the nucleus where they are translated into proteins by ribosomes.

hnRNA is 4 to 10 times more complex than mRNA. hnRNA has non random and sequence-dependent ribonucleoproteins.

Regulatory RNAs

MicroRNAs (miRNA)

A miRNA (micro-RNA) is a form of single-stranded RNA which consists of short stretch of RNA which is 20-25 nucleotide long. It is found in all eukaryotic cells. They were initally believed to regulate the expression of other genes. But it is now clear that they are post transcriptional regulators which are complementary to the target mRNA sequence. miRNAs are RNA genes which are transcribed from DNA, but are not translated into protein. They function to translational repression and gene silencing.

Structure

The DNA sequence that codes for an miRNA gene is longer than the miRNA itself. This DNA sequence includes the miRNA sequence and an approximate reverse complement. When this DNA sequence is transcribed into a single-stranded RNA molecule, the miRNA sequence and its reverse-complement base pair to form a double stranded RNA hairpin loop; this forms a primary miRNA structure (pri-miRNA).

In animals, the nuclear enzyme Drosha cleaves the base of the hairpin to form pre-miRNA. The pre-miRNA molecule is then actively transported out of the nucleus into the cytoplasm by Exportin 5, a carrier protein. The Dicer enzyme then cuts 20-25 nucleotides from the base of the hairpin to release the mature miRNA.

In plants, which lack Drosha homologues, pri- and pre-miRNA processing by Dicer probably takes place in the nucleus, and mature miRNA duplexes are exported to the cytosol by Exportin 5. The pre-miRNA molecule is then actively transported out of the nucleus into the cytoplasm by Exportin 5, a carrier protein. The Dicer enzyme then cuts 20-25 nucleotides from the base of the hairpin to release the mature miRNA. The miRNA in plants has a perfect complimentarity with its target mRNA with a few mismatches.

Figure 5. showing structure of miRNA

Figure 6. showing synthesis and maturation of miRNA

Functions

They are primarily involved in regulation of gene expression. That is why miRNA sequence is complemntary to a part of mRNA or to one or more mRNAs. Animal miRNAs are complemntary to the mRNA at a site in 3' UTR whereas plant miRNAs are complementary to the coding region of mRNA. miRNA regulate gene expression by binding to complementary sequence on the mRNA which prevents mRNA from being translated, sometimes it also causes cleavage of mRNA.

miRNA with partial complimentarity to its target can degrade mRNA by speeding up deadenylation. Sometimes miRNA also cause histone modification and DNA methylation at promoter site interfering the expression of targeted genes.

MicroRNAs are significant phylogenetic markers because of their astonishingly low rate of evolution. MicroRNAs originate predominantly by the random formation of hairpins in "non-coding" regions of DNA, but also by the duplication and modification of existing microRNAs. Once a microRNA gains a function it undergoes extreme purifying selection and are rarely lost. This make them ideal candidate to serve as phylogentic markers.

Small interfering RNAs (siRNA)

Small interfering RNAs are also known as short interfering RNA. They are a short stretch of 20-25 nucleotide-long RNA molecules that interfere with the expression of genes. They are synthesized during RNA interference (RNAi) pathway by the enzyme Dicer. They find extensive use in labs to study particular gene function, by knocking them down.

Structure

siRNA's have a short of 20-22 nucleotides, double-strand of RNA (dsRNA) with 2-nucleotides overhangs on either end, including a 5' phosphate group and a 3' hydroxy (-OH) group.

RNA polymerase III promoter, which direct the transcription of small nuclear RNA's. The resulting molecule has a short hairpin RNA transcript which is further processed by dicer enzyme.

Introduction of too much siRNA can result in non-specific events due to activation of the interferon pathway. One method of reducing the non-specific effects of siRNA is by turning the shRNA into a micro RNA. Since miRNA's are naturally occurring and well tolerated by the cell. So by engineering a siRNA sequence into a miRNA structure, non-specific effects can be eliminated.

Figure 7. showing action of siRNA

Function

The mediators of RNA interference are 21- and 23-nucleotide small interfering RNAs (siRNA). siRNAs bind to a ribonuclease complex called RNA-induced silencing complex (RISC) that guides the small dsRNAs to its homologous mRNA target. Consequently, RISC cuts the mRNA approximately in the middle of the region paired with the antisense siRNA, after which the mRNA is further degraded.

Piwi-interacting RNAs (piRNA)

Argonaute are a class of proteins which are essential components of small RNA silencing pathways. Base on the similarities in argonaute protein , it can be divided into AGO and PIWI. piRNAs are the largest class of novel small RNAs which binds specifically to PIWI type of Argonaute proteins, in animals. Both PIWI type of Argonaute proteins and piRNAs are expressed in gonads of animals where they play a crucial role in transcriptional gene silencing of retrotransposons and maintains integrity of genome during gametogenesis.

Structure of piRNA

piRNAs have been found clustered throughout the genome and each cluster contains 10-10,000 of piRNA. The clustering of piRNA is highly conserved across the species. piRNA have been found out at cytoplasm and nucleus suggesting their role in both cytoplasmic and nuclear processes.

piRNAs are found both in vertebrates and invertebrates, though their biogenesis is not very clear. piRNAs have no clear secondary structure motifs, the length of a piRNA is between 26 and 31 nucleotides, and the presence of a 5’ uridine is common to piRNAs in both vertebrates and invertebrates. piRNAs in C. elegans have a 5’ monophosphate and a 3’ modification that acts to block either the 2’ or 3’ oxygen.

Figure 8. showing proposed structure of piRNA

Function

piRNAs have been known to act as gene silencers specifically of transposons. Their antisense sequences to transposons further strengthens the statement. In mammals, the activity of piRNAs in transposon silencing is most important during the development of the embryo, and in both C. elegans and humans, piRNAs are necessary for spermatogenesis.

Based on research in D.melanogaster, piRNAs may be involved in maternally derived epigenetic effects. The activity of specific piRNAs in the epigenetic process also requires interactions between Piwi proteins and HP1a, as well as other factors.

CRISPR RNAs

Clustered regularly interspaced short palindromic repeats (CRISPR) RNA. They belong to a class of RNA regulator, which act through base pairing with RNA. They function to influence the translation and stability of mRNAs. CRISPR systems have some similarities with eukaryotic siRNA-driven gene silencing, although they exhibit distinct features as well. They are found in the genomes of a few bacteria and in most of archaea.

Structure of CRISPR RNA

CRISPR contains sequences which are highly variable DNA regions that consist of ~550 bp leader sequence followed by a series of repeat-spacer units. The repeated DNA can vary from 24 to 47 base pairs, but the same repeat sequence usually appears in each unit in a given CRISPR array and is repeated 2 to 249 times. Adjacent to the CRISPR DNA array are several CRISPR-associated (CAS) genes. Two to six core CAS genes seem to be associated with most CRISPR systems, but different CRISPR subtypes also have specific CAS genes encoded in the flanking region.

Function

CRISPR RNAs interfere with bacteriophage infection and plasmid conjugation and provide a kind of immunity against infection. They do so by targeting the homologous foreign DNA through an unknown mechanism. But, few researchers have a belief that they provide immunity by integrating foreign DNA in between the repeat sequences in the CRISPR locus of the prokaryote. The integrated DNA sequence is then used by the CRISPR system to identify and silence exogenous genetic elements in a manner analogous to RNAi in eukaryotic organisms.

The molecular functions of the CAS proteins are still not clearly known but they are contain RNA- or DNA-binding domains,helicase motifs, and endo- or exonuclease domains.

Recent findings suggests that CAS genes encode for proteins which have function similar to eukaryotic RNAi enzymes. The CRISPR DNA array is transcribed into a long RNA, which is processed by the Cascade complex of CAS proteins into a single repeat-spacer unit known as a crRNA. crRNAs would target DNA or RNA, but CRISPR spacers generated from both strands of phage genes can effectively confer phage resistance.

Figure 9. showing gene arrangement and regulatory function of CRISPR RNAs

CRISPR arrays are composed of DNA repeats (triangles) separated by unique spacers (speckled boxes). CAS genes (blue), which encode proteins that function in CRISPR RNA processing and/or DNA silencing, are located nearby. The CRISPR arrays are initially transcribed as a long RNA, which is subsequently processed by the Cascade complex (blue circles and ovals) to individual repeat-spacer units, called crRNAs. These crRNAs appear to target foreign DNA through an unknown mechanism likely involving other CAS proteins and the degradation of the exogenous DNA

The CRISPR system finds a wide use in evolutionary studies. The extreme variability of CRISPR arrays between organisms and even strains of the same species makes it a useful tool for genotype strains and to study horizontal gene transfer and microevolution.

The ability of CRISPR system to record the history of recent phage infection and allow differentiation between strains of the same species. This unique ability of system can be used to identify pathogenic bacterial strains and track disease progression worldwide, as well as to monitor the population dynamics of nonpathogenic bacteria.

RNAs in RNA processing

small nuclear RNAs (snRNA)

Small nuclear ribonucleic acid (snRNA) is a class of small RNA molecules that are found only within the nucleus, they are ~100bp. They are transcribed by RNA polymerase II or RNA polymerase III. They are

generally associated with nuclear proteins to perform some other function (e.g. pre-mRNA splicing or telomere maintainance) like regulation of transcription factors (7SK RNA) or RNA polymerase II (B2 RNA), and maintaining the telomeres. They found in association with specific proteins and together they form a complex known as small nuclear ribonucleoproteins (snRNP). snRNA have modifications other than 5’cap and 3’ poly (A) tail depending on their function.

Function

snRNAs serve as recognition molecules for intron splice sites. They play an important role in telomere maintenance. Telomerase is special among polymerases in that it can synthesize DNA without a template. It is able to do this because telomerase is actually a ribonucleoprotein -- a combination of protein and RNA. Telomerase contains a ~150 nucleotide RNA subunit which serves as a template for the telomere sequence. With this internal RNA template, telomerase can accurately extend the telomere sequence and help maintain the chromosomes' telomeres. The RNA subunit in telomerase is a small nuclear RNA.

Small nucleolar RNAs (snoRNA)

Small nucleolar RNAs are a class of small RNA molecules that has a main function to guide chemical modifications of other RNAs, mainly ribosomal RNAs, transfer RNAs and small nuclear RNAs. There are two main classes of snoRNA, the C/D box snoRNAs which are associated with methylation, and the H/ACA box snoRNAs which are associated with pseudouridylation.

Function of snoRNA

Each snoRNA molecule can guide the modification on only one or in some cases two individual RNA molecule. To carry out modification of RNA, snoRNA interacts with at least four protein molecules and forms a RNA/protein complex known as a small nucleolar ribonucleoprotein (snoRNP). snoRNA molecules are basically a stretch of 10-20 nucleotides (antisense element) which are complementary to the bases on the target pre-mRNA to be modified. In this way snoRNP recognizes and binds to target RNA. Once the snoRNP has bound to the target site the associated proteins are in the correct physical location to catalyse the chemical modification of the target base.

A B

Figure 10. showing structure of snoRNAs. A. C/D Box and b. H/ACA Box.

Other functions of snoRNA

snoRNAs can also function as miRNAs. It has been shown that human ACA45 is a bona fide snoRNA that can be processed into a 21 nucleotides long mature miRNA by the RNAse III family endoribonuclease dicer.

Recently, it has been found that snoRNAs can have functions not related to rRNA. One such function is the regulation of alternative splicing of the trans gene transcript.

RNAs as enzyme

Ribozymes

A ribozyme can be defined as an RNA molecule which has the capacity to catalyze a chemical reaction in the absence of catalyzing enzymes (proteins). Ribozymes promote the reaction by increasing their rate of reaction. Catalytic RNA fold themselves into a 3D structure and they catalyze the transesterification reaction of phosphate diester and participate in RNA maturation or processing. But majority of RNAs known perform the function of autocatalysis. The discovery of ribozymes have suggest that ribozymes would have contributed to self replication and protein synthesis in early evolution and this idea suggesting the role of RNA in evolution has been termed as RNA World hypothesis.

Catalytic RNAs are found in various biological areas like small catalytic RNAs were found in the hammerhead, the hairpin, the hepatitis delta virus (HDV), and the Varkud satellite (VS) ribozymes. All these RNAs perform the same function but they differ in their secondary and tertiary structures. In each case, the satellite RNA is believed to replicate via a complementary RNA intermediate by a rolling circle mechanism. The ribozymes participate in the replication by self-cleaving the tandem satellite repeats into monomer units.

Second and more common type of catalytic RNA consists of self-splicing introns. These types of RNAs provide the active site necessary to complete their own RNA splicing from an RNA transcipt. Based on their differences in conserved structure and reaction mechanism they are divided into two groups. In addition to splicing, both classes of introns can catalyze reverse splicing reactions, which allows them to act as mobile elements for the horizontal transfer of genetic information.

Third type of ribozymes is ribonuclease P (RNase P). They participate in transfer RNA processing. It acts in trans to catalyze the removal of nucleotides from the 5′-end of the pre-tRNA. The celular form of this enzyme consists of both an RNA and a protein component. It is an holoenzyme where catalytic function is carried out by RNA while protein part increases rate of its catalytic function.

Structure of Catalytic RNA

Catalytic RNA consist of a three-dimensional arrangement of nucleotides, metal ions, water molecules and co-factors. But in reality catalytic RNA acquire more complex structures tan simple single stranded RNA.RNA can form a pseudo base pair between two consecutive A nucleotides in a single-stranded region (termed an A-platform) that serves as a platform for tertiary helix-stacking interactions. There are also examples of pseudoknots, G · U wobble pairing receptors, GAAA tetraloops, and U-turns. The consensus sequences of these structural motifs are seen repeatedly in the phylogenetic database, which suggests that they have been used as building blocks to create a variety of RNA structures.

Non coding RNA (ncRNA)

A non-coding RNA is a functional RNA molecule that functions without being translated into a protein. E.g. tRNA, rRNA. It is also known as non-protein-coding RNA (npcRNA), non-messenger RNA (nmRNA), small non-messenger RNA (snmRNA) and functional RNA (fRNA) but this does not mean that such RNAs do not contain information nor have function. Although it has been generally assumed that most genetic information is transacted by proteins, recent evidence suggests that the majority of the genomes of mammals and other complex organisms is in fact transcribed into ncRNAs, many of which are alternatively spliced and/or processed into smaller products. These ncRNAs include microRNAs and snoRNAs (many if not most of which remain to be identified), as well as likely other classes of yet-to-be-discovered small regulatory RNAs, and tens of thousands of longer transcripts (including complex patterns of interlacing and overlapping sense and antisense transcripts), most of whose functions are unknown.

Non-coding RNA genes include highly abundant and functionally important RNAs such as transfer RNA (tRNA) and ribosomal RNA (rRNA), as well as RNAs such as snoRNAs, miRNA , siRNA and piRNA and the long ncRNAs that include examples such as Xist and HOTAIR.

Functions

It has been already known that ncRNA are functional in control of chromosome dynamics, RNA editing, translational inhibition and mRNA destruction. RNA signaling underpins chromatin remodeling and epigenetic memory, although the mechanisms are unknown. transcription itself may be regulated by ncRNAs. As noted earlier, RNA polymerase II itself appears to be regulated in part by ncRNA signaling. A ncRNA has been reported to be required for the repression of RNA polymerase II-dependent transcription in primordial germ cells in Drosophila. ncRNAs also play a role in stress responses. The small noncoding transcript B2 is produced by RNA polymerase III from murine short interspersed elements (SINE) under heat shock. ncRNAs may also act as scaffolding for the assembly of macromolecular complexes. Examples include rRNA in ribosomes.

Recent discovery also show, the existence of snoRNA, microRNA, piRNA characteristics in a novel non-coding RNA: x-ncRNA.

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