RNA Totally Explained

Everything about Ribonucleic Acid totally explained

Ribonucleic acid or RNA is a nucleic acid made from a long chain of nucleotide units. Each nucleotide consists of a nitrogenous base, a ribose sugar, and a phosphate. RNA is very similar to DNA, but differs in a few important structural details: in the cell RNA is usually single stranded, while DNA is usually double stranded. RNA nucleotides contain ribose while DNA contains deoxyribose (a type of ribose that lacks one oxygen atom), and RNA has the nucleotide uracil rather than thymine which is present in DNA.
RNA is transcribed from DNA by enzymes called RNA polymerases and is generally further processed by other enzymes. Some of these RNA-processing enzymes contain RNA as part of their structures. RNA is also central to the translation of some RNAs into proteins. In this process, a type of RNA called messenger RNA carries information from DNA to structures called ribosomes. These ribosomes are made from proteins and ribosomal RNAs, which come together to form a molecular machine that can read messenger RNAs and translate the information they carry into proteins. It has also been known since the 1990s that several types of RNA regulate which genes are active.

Structure

Each nucleotide in RNA contains a ribose sugar, with carbons numbered 1' through 5'. A base is attached to the 1' position, generally adenine (A), cytosine (C), guanine (G) or uracil (U). Adenine and guanine are purines, cytosine and uracil are pyrimidines. A phosphate group is attached to the 3' position of one ribose and the 5' position of the next. The phosphate groups have a negative charge each at physiological pH, making RNA a charged molecule (polyanion). The bases may form hydrogen bonds between cytosine and guanine, between adenine and uracil and between guanine and uracil. or the GNRA tetraloop that has a guanine–adenine base-pair. An important structural feature of RNA that distinguishes it from DNA is the presence of a hydroxyl group at the 2' position of the ribose sugar. The presence of this functional group causes the helix to adopt the A-form geometry rather than the B-form most commonly observed in DNA. This results in a very deep and narrow major groove and a shallow and wide minor groove. A second consequence of the presence of the 2'-hydroxyl group is that in conformationally flexible regions of an RNA molecule (that is, not involved in formation of a double helix), it can chemically attack the adjacent phosphodiester bond to cleave the backbone.
RNA is transcribed with only four bases (adenine, cytosine, guanine and uracil), but there are numerous modified bases and sugars in mature RNAs. Pseudouridine (Ψ), in which the linkage between uracil and ribose is changed from a C–N bond to a C–C bond, and ribothymidine (T), are found in various places (most notably in the TΨC loop of tRNA). Another notable modified base is hypoxanthine, a deaminated adenine base whose nucleoside is called inosine. Inosine plays a key role in the wobble hypothesis of the genetic code. There are nearly 100 other naturally occurring modified nucleosides, of which pseudouridine and nucleosides with 2'-O-methylribose are the most common. The specific roles of many of these modifications in RNA are not fully understood. However, it's notable that in ribosomal RNA, many of the post-transcriptional modifications occur in highly functional regions, such as the peptidyl transferase center and the subunit interface, implying that they're important for normal function. The functional form of single stranded RNA molecules, just like proteins, frequently requires a specific tertiary structure. The scaffold for this structure is provided by secondary structural elements which are hydrogen bonds within the molecule. This leads to several recognizable "domains" of secondary structure like hairpin loops, bulges and internal loops. There has been a significant amount of research directed at the RNA structure prediction problem.

Comparison with DNA

RNA and DNA differ in three main ways. First, unlike DNA which is double-stranded, RNA is a single-stranded molecule in most of its biological roles and has a much shorter chain of nucleotides. Second, while DNA contains deoxyribose, RNA contains ribose, (there is no hydroxyl group attached to the pentose ring in the 2' position in DNA). These hydroxyl groups make RNA less stable than DNA because it's more prone to hydrolysis. Third, the complementary nucleotide to adenine isn't thymine, as it's in DNA, but rather uracil, which is an unmethylated form of thymine. For instance, determination of the structure of the ribosome—an enzyme that catalyzes peptide bond formation—revealed that its active site is composed entirely of RNA.

Synthesis

Synthesis of RNA is usually catalyzed by an enzyme—RNA polymerase—using DNA as a template, a process known as transcription. Initiation of transcription begins with the binding of the enzyme to a promoter sequence in the DNA (usually found "upstream" of a gene). The DNA double helix is unwound by the helicase activity of the enzyme. The enzyme then progresses along the template strand in the 3’ to 5’ direction, synthesizing a complementary RNA molecule with elongation occurring in the 5’ to 3’ direction. The DNA sequence also dictates where termination of RNA synthesis will occur.
RNAs are often modified by enzymes after transcription. For example, a poly(A) tail and a 5' cap are added to eukaryotic pre-mRNA.
There are also a number of RNA-dependent RNA polymerases as well that use RNA as their template for synthesis of a new strand of RNA. For instance, a number of RNA viruses (such as poliovirus) use this type of enzyme to replicate their genetic material. Also, it's known that RNA-dependent RNA polymerases are required for the RNA interference pathway in many organisms.

Types of RNA

Overview

Messenger RNA (mRNA) is the RNA that carries information from DNA to the ribosome, the sites of protein synthesis (translation) in the cell. The coding sequence of the mRNA determines the amino acid sequence in the protein that's produced. There are also non-coding RNAs involved in gene regulation, RNA processing and other roles. Certain RNAs are able to catalyse chemical reactions such as cutting and ligating other RNA molecules, and the catalysis of peptide bond formation in the ribosome; rRNA is extremely abundant and makes up 80% of the 10 mg/ml RNA found in a typical eukaryotic cytoplasm. Transfer-messenger RNA (tmRNA) is found in many bacteria and plastids. It tags proteins encoded by mRNAs that lack stop codons for degradation and prevents the ribosome from stalling.

In gene regulation

Several types of RNA can downregulate gene expression by being complementary to a part of an mRNA or gene. MicroRNAs (miRNA; 21-22 nt) are found in eukaryotes and act through RNA interference (RNAi), where an effector complex of miRNA and enzymes can break down mRNA which the miRNA is complementary to, block the mRNA from being translated, or cause a promoter to be methylated which generally downregulates its gene. Some miRNAs upregulate genes instead (RNA activation). While small interfering RNAs (siRNA; 20-25 nt) are often produced by breakdown of viral RNA, there are also endogenous sources of siRNAs in plants. siRNAs act through RNA interference in a fashion similar to miRNAs, including RNA activation. Animals have Piwi-interacting RNAs (piRNA; 29-30 nt) which are active in germline cells and are thought to be a defense against transposons and play a role in gametogenesis. Antisense RNAs are widespread among bacteria; most downregulate a gene, but a few are activators of transcription. Antisense RNA acts by binding to an mRNA, forming double-stranded RNA that's degraded by enzymes. There are many mRNA-like large non-coding RNAs that regulate genes in eukaryotes, one such RNA is Xist which coats one X chromosome in female mammals and inactivates it.
An mRNA may contain regulatory elements itself, such as riboswitches, in the 5' UTR or 3' UTR; these cis-regulatory elements regulate the activity of that mRNA.

In RNA processing

Many RNAs are involved in modifying other RNAs. Introns are spliced out of pre-mRNA by spliceosomes, which contain several small nuclear RNAs (snRNA), RNA can also be altered by having its nucleotides modified to other nucleotides than A, C, G and U. In eukaryotes, modifications of RNA nucleotides are generally directed by small nucleolar RNAs (snoRNA; 60-300 nt), found in the nucleolus and cajal bodies. snoRNAs associate with enzymes and guide them to a spot on an RNA by basepairing to that RNA. These enzymes then perform the nucleotide modification. rRNAs and tRNAs are extensively modified, but snRNAs and mRNAs can also be the target of base modification.

RNA genomes

Like DNA, RNA can be an information carrier. RNA viruses have genomes composed of RNA, plus a variety of proteins encoded by that genome. The viral genome is replicated by some of those proteins, while other proteins protect the genome as the virus particle moves to a new host cell. Viroids are another group of pathogens, but they consist only of RNA, don't encode any protein and are replicated by a host plant cell's polymerase.

In reverse transcription

Reverse transcribing viruses replicate their genomes by reverse transcribing DNA copies from their RNA; these DNA copies are then transcribed to new RNA. Retrotransposons also spread by copying DNA and RNA from one another, and telomerase contains an RNA that's used as template for building the ends of eukaryotic chromosomes.

Double-stranded RNA

Double-stranded RNA (dsRNA) is RNA with two complementary strands, similar to the DNA found in all cells. dsRNA forms the genetic material of some viruses (double-stranded RNA viruses). Double-stranded RNA such as viral RNA or siRNA can trigger RNA interference in eukaryotes, as well as interferon response in vertebrates.

Discovery

Nucleic acids were discovered in 1868 by Friedrich Miescher, who called the material 'nuclein' since it was found in the nucleus. It was later discovered that prokaryotic cells, which don't have a nucleus, also contain nucleic acids. The role of RNA in protein synthesis had been suspected since 1939. The first eukaryotic messenger RNA, for rabbit hemoglobin, was isolated in 1967 and was found to induce the synthesis of hemoglobin after injection into oocytes. Severo Ochoa won the 1959 Nobel Prize in Medicine after he discovered how RNA is synthesized. The sequence of the 77 nucleotides of a yeast tRNA was found by Robert W. Holley in 1965, winning Holley the 1968 Nobel Prize in Medicine. Carl Woese realised RNA can be catalytic in 1967 and proposed the earliest forms of life relied on RNA both to carry genetic information and to catalyze biochemical reactions—an RNA world. In 1976, Walter Fiers and his team at the University of Ghent determined the first complete nucleotide sequence of an RNA virus genome, that of bacteriophage MS2. In the early 1990s it was found that introduced genes can silence homologous endogenous genes in plants. At about the same time, 22 nt long RNAs, now known as microRNAs, were found to have a role in the development of C. elegans. The discovery of gene regulatory RNAs has led to attempts to develop drugs made of RNA, like siRNA, particularly to silence oncogenes and viral genes.