RNA
From DrugPedia: A Wikipedia for Drug discovery
Template:Reference from where original matirial taken
Ribonucleic acid (RNA) is a nucleic acid and consists of 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 base 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. RNA is central to the synthesis of proteins. Here, 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. There are RNAs with other roles – in particular regulating which genes are expressed, but also as the genome of most viruses.
Contents |
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.<ref name="pmid15561141"/> However other interactions are possible, such as a group of adenine bases binding to each other in a bulge,<ref>Template:Cite book</ref> or the GNRA tetraloop that has a guanine–adenine base-pair.<ref name="pmid15561141">Lee JC, Gutell RR (2004). "Diversity of base-pair conformations and their occurrence in rRNA structure and RNA structural motifs". J. Mol. Biol. 344 (5): 1225–49. doi:. PMID 15561141.</ref>
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.<ref>Salazar M, Fedoroff OY, Miller JM, Ribeiro NS, Reid BR (1992). "The DNA strand in DNAoRNA hybrid duplexes is neither B-form nor A-form in solution". Biochemistry 32 (16): 4207–15. doi:. PMID 7682844.</ref> This results in a very deep and narrow major groove and a shallow and wide minor groove.<ref>Hermann T, Patel DJ (2000). "RNA bulges as architectural and recognition motifs". Structure 8 (3): R47. doi:. PMID 10745015.</ref> 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.<ref>Mikkola S, Nurmi K, Yousefi-Salakdeh E, Strömberg R, Lönnberg H (1999). "The mechanism of the metal ion promoted cleavage of RNA phosphodiester bonds involves a general acid catalysis by the metal aquo ion on the departure of the leaving group". Perkin transactions 2: 1619–26. doi:.</ref>
RNA is transcribed with only four bases (adenine, cytosine, guanine and uracil),<ref>Template:Cite book</ref> 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).<ref>Yu Q, Morrow CD (2001). "Identification of critical elements in the tRNA acceptor stem and TΨC loop necessary for human immunodeficiency virus type 1 infectivity". J Virol. 75 (10): 4902–6. doi:. PMID 11312362.</ref> 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.<ref>Elliott MS, Trewyn RW (1983). "Inosine biosynthesis in transfer RNA by an enzymatic insertion of hypoxanthine". J. Biol. Chem. 259 (4): 2407–10. PMID 6365911.</ref> There are nearly 100 other naturally occurring modified nucleosides,<ref>Template:Cite book</ref> of which pseudouridine and nucleosides with 2'-O-methylribose are the most common.<ref>Kiss T (2001). "Small nucleolar RNA-guided post-transcriptional modification of cellular RNAs". The EMBO Journal 20: 3617–22. doi:. PMID 11447102.</ref> The specific roles of many of these modifications in RNA are not fully understood. However, it is 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 are important for normal function.<ref>King TH, Liu B, McCully RR, Fournier MJ (2002). "Ribosome structure and activity are altered in cells lacking snoRNPs that form pseudouridines in the peptidyl transferase center". Molecular Cell 11 (2): 425–35. doi:. PMID 12620230.</ref>
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.<ref>Mathews DH, Disney MD, Childs JL, Schroeder SJ, Zuker M, Turner DH (2004). "Incorporating chemical modification constraints into a dynamic programming algorithm for prediction of RNA secondary structure". Proc. Natl. Acad. Sci. USA 101 (19): 7287–92. doi:. PMID 15123812.</ref> Since RNA is charged, metal ions such as Mg2+ are needed to stabilise many secondary structures.<ref>Tan ZJ, Chen SJ (2008). "Salt dependence of nucleic acid hairpin stability". Biophys. J. 95: 738–52. doi:. PMID 18424500.</ref>
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 is more prone to hydrolysis. Third, the complementary base to adenine is not thymine, as it is in DNA, but rather uracil, which is an unmethylated form of thymine.<ref name=Biochemistry/>
Like DNA, most biologically active RNAs including tRNA, rRNA, snRNAs and other, non-coding, RNAs are extensively base paired to form double stranded helices. Structural analysis of these RNAs have revealed that they are highly structured. Unlike DNA, this structure is not long double-stranded helices but rather collections of short helices packed together into structures akin to proteins. In this fashion, RNAs can achieve chemical catalysis, like enzymes.<ref>Higgs PG (2000). "RNA secondary structure: physical and computational aspects". Quarterly Reviews of Biophysics 33: 199–253. doi:. PMID 11191843.</ref> 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.<ref name=ribosome_activity>Nissen P, Hansen J, Ban N, Moore PB, Steitz TA (2000). "The structural basis of ribosome activity in peptide bond synthesis". Science 289 (5481): 920–30. doi:. PMID 10937990.</ref>
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.<ref>Nudler E, Gottesman ME (2002). "Transcription termination and anti-termination in E. coli". Genes to Cells 7: 755–68. doi:. PMID 12167155.</ref>
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 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.<ref>Jeffrey L Hansen, Alexander M Long, Steve C Schultz (1997). "Structure of the RNA-dependent RNA polymerase of poliovirus". Structure 5 (8): 1109-22. doi:. PMID 9309225.</ref> Also, it is known that RNA-dependent RNA polymerases are required for the RNA interference pathway in many organisms.<ref>Ahlquist P (2002). "RNA-Dependent RNA Polymerases, Viruses, and RNA Silencing". Science 296 (5571): 1270–73. doi:. PMID 12016304.</ref>
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 is produced.<ref name=The_Cell/> Many RNAs do not code for protein however. These non-coding RNAs can be encoded by their own genes (RNA genes), but can also derive from mRNA introns.<ref name=transcriptome/> The most prominent examples of non-coding RNAs are transfer RNA (tRNA) and ribosomal RNA (rRNA), both of which are involved in the process of translation.<ref name=Biochemistry>Template:Cite book</ref> 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,<ref>Rossi JJ (2004). "Ribozyme diagnostics comes of age". Chemistry & Biology 11 (7): 894–95. doi:.</ref> and the catalysis of peptide bond formation in the ribosome;<ref name=ribosome_activity/> these are known as ribozymes.
In translation
Messenger RNA (mRNA) carries information about a protein sequence to the ribosomes, the protein synthesis factories in the cell. It is coded so that every three nucleotides (a codon) correspond to one amino acid. In eukaryotic cells, once precursor mRNA (pre-mRNA) has been transcribed from DNA, it is processed to mature mRNA. This removes its introns—non-coding sections of the pre-mRNA. The mRNA is then exported from the nucleus to the cytoplasm, where it is bound to ribosomes and translated into its corresponding protein form with the help of tRNA. In prokaryotic cells, which do not have nucleus and cytoplasm compartments, mRNA can bind to ribosomes while it is being transcribed from DNA. After a certain amount of time the message degrades into its component nucleotides with the assistance of ribonucleases.<ref name=The_Cell/>
Transfer RNA (tRNA) is a small RNA chain of about 80 nucleotides that transfers a specific amino acid to a growing polypeptide chain at the ribosomal site of protein synthesis during translation. It has sites for amino acid attachment and an anticodon region for codon recognition that binds to a specific sequence on the messenger RNA chain through hydrogen bonding.<ref name=transcriptome/>
Ribosomal RNA (rRNA) is the catalytic component of the ribosomes. Eukaryotic ribosomes contain four different rRNA molecules: 18S, 5.8S, 28S and 5S rRNA. Three of the rRNA molecules are synthesized in the nucleolus, and one is synthesized elsewhere. In the cytoplasm, ribosomal RNA and protein combine to form a nucleoprotein called a ribosome. The ribosome binds mRNA and carries out protein synthesis. Several ribosomes may be attached to a single mRNA at any time.<ref name=The_Cell>Template:Cite book</ref> rRNA is extremely abundant and makes up 80% of the 10 mg/ml RNA found in a typical eukaryotic cytoplasm.<ref>Kampers T, Friedhoff P, Biernat J, Mandelkow E-M, Mandelkow E (1996). "RNA stimulates aggregation of microtubule-associated protein tau into Alzheimer-like paired helical filaments". FEBS Letters 399: 104D. doi:. PMID 8985176.</ref>
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.<ref>Gueneau de Novoa P, Williams KP (2004). "The tmRNA website: reductive evolution of tmRNA in plastids and other endosymbionts". Nucleic Acids Res. 32 (Database issue): D104–8. doi:. PMID 14681369.</ref>
Regulatory RNAs
Several types of RNA can downregulate gene expression by being complementary to a part of an mRNA or a gene's DNA. 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 accelerate its degradation.<ref>Wu L, Belasco JG (January 2008). "Let me count the ways: mechanisms of gene regulation by miRNAs and siRNAs". Mol. Cell 29 (1): 1–7. doi:. PMID 18206964.</ref><ref>Matzke MA, Matzke AJM (2004). "Planting the seeds of a new paradigm". PLoS Biology 2 (5): e133. doi:. PMID 15138502.</ref> 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.<ref>Vazquez F, Vaucheret H, Rajagopalan R, Lepers C, Gasciolli V, Mallory AC, Hilbert J, Bartel DP, Crété P (2004). "Endogenous trans-acting siRNAs regulate the accumulation of Arabidopsis mRNAs". Molecular Cell 16 (1): 69–79. doi:. PMID 15469823.</ref> siRNAs act through RNA interference in a fashion similar to miRNAs. Some miRNAs and siRNAs can cause genes they target to be methylated, thereby decreasing or increasing transcription of those genes.<ref>Sontheimer EJ, Carthew RW (July 2005). "Silence from within: endogenous siRNAs and miRNAs". Cell 122 (1): 9–12. doi:. PMID 16009127.</ref><ref>Doran G (2007). "RNAi – Is one suffix sufficient?". Journal of RNAi and Gene Silencing 3 (1): 217–19.</ref><ref>Pushparaj PN, Aarthi JJ, Kumar SD, Manikandan J (2008). "RNAi and RNAa - The Yin and Yang of RNAome". Bioinformation 2 (6): 235–7. PMID 18317570.</ref> 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.<ref name=fruitfly_piRNA>Horwich MD, Li C Matranga C, Vagin V, Farley G, Wang P, Zamore PD (2007). "The Drosophila RNA methyltransferase, DmHen1, modifies germline piRNAs and single-stranded siRNAs in RISC". Current Biology 17: 1265–72. doi:. PMID 17604629.</ref><ref>Girard A, Sachidanandam R, Hannon GJ, Carmell MA (2006). "A germline-specific class of small RNAs binds mammalian Piwi proteins". Nature 442: 199–202. doi:. PMID 16751776.</ref> Antisense RNAs are widespread among bacteria; most downregulate a gene, but a few are activators of transcription.<ref>Wagner EG, Altuvia S, Romby P (2002). "Antisense RNAs in bacteria and their genetic elements". Adv Genet. 46: 361–98. doi:. PMID 11931231.</ref> Antisense RNA can act by binding to an mRNA, forming double-stranded RNA that is degraded by enzymes.<ref>Template:Cite book</ref> There are many mRNA-like large non-coding RNAs that regulate genes in eukaryotes,<ref>Hüttenhofer A, Schattner P, Polacek N (2005). "Non-coding RNAs: hope or hype?". Trends Genet. 21 (5): 289–97. doi:. PMID 15851066.</ref> one such RNA is Xist which coats one X chromosome in female mammals and inactivates it.<ref>Heard E, Mongelard F, Arnaud D, Chureau C, Vourc'h C, Avner P (1999). "Human XIST yeast artificial chromosome transgenes show partial X inactivation center function in mouse embryonic stem cells". Proc. Natl. Acad. Sci. USA 96 (12): 6841–46. doi:. PMID 10359800.</ref>
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.<ref>Batey RT (2006). "Structures of regulatory elements in mRNAs". Curr. Opin. Struct. Biol. 16 (3): 299–306. doi:. PMID 16707260.</ref>
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),<ref name=Biochemistry/> or the introns can be ribozymes that are spliced by themselves.<ref>Steitz TA, Steitz JA (1993). "A general two-metal-ion mechanism for catalytic RNA". Proc. Natl. Acad. Sci. U.S.A. 90 (14): 6498–502. doi:. PMID 8341661.</ref> 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),<ref name=transcriptome>Template:Cite book</ref> 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.<ref>Xie J, Zhang M, Zhou T, Hua X, Tang L, Wu W (2007). "Sno/scaRNAbase: a curated database for small nucleolar RNAs and cajal body-specific RNAs". Nucleic Acids Res. 35: D183–7. doi:. PMID 17099227.</ref><ref>Omer AD, Ziesche S, Decatur WA, Fournier MJ, Dennis PP (2003). "RNA-modifying machines in archaea". Molecular Microbiology 48 (3): 617–29. doi:. PMID 12694609.</ref>
RNA genomes
Like DNA, RNA can carry genetic information. 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, do not encode any protein and are replicated by a host plant cell's polymerase.<ref>Daròs JA, Elena SF, Flores R (2006). "Viroids: an Ariadne's thread into the RNA labyrinth". EMBO Rep. 7 (6): 593–8. doi:. PMID 16741503.</ref>
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,<ref>Kalendar R, Vicient CM, Peleg O, Anamthawat-Jonsson K, Bolshoy A, Schulman AH (2004). "Large retrotransposon derivatives: abundant, conserved but nonautonomous retroelements of barley and related genomes". Genetics 166 (3): D339. doi:. PMID 15082561.</ref> and telomerase contains an RNA that is used as template for building the ends of eukaryotic chromosomes.<ref>Podlevsky JD, Bley CJ, Omana RV, Qi X, Chen JJ (2008). "The telomerase database". Nucleic Acids Res. 36 (Database issue): D339–43. doi:. PMID 18073191.</ref>
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.<ref>Blevins T et al (2006). "Four plant Dicers mediate viral small RNA biogenesis and DNA virus induced silencing". Nucleic Acids Res 34 (21): 6233–46. doi:. PMID 17090584.</ref><ref>Jana S, Chakraborty C, Nandi S, Deb JK (2004). "RNA interference: potential therapeutic targets". Appl. Microbiol. Biotechnol. 65 (6): 649–57. doi:. PMID 15372214.</ref><ref>Schultz U, Kaspers B, Staeheli P (2004). "The interferon system of non-mammalian vertebrates". Dev. Comp. Immunol. 28 (5): 499–508. doi:. PMID 15062646.</ref>
Discovery
Nucleic acids were discovered in 1868 by Friedrich Miescher, who called the material 'nuclein' since it was found in the nucleus.<ref>Dahm R (2005). "Friedrich Miescher and the discovery of DNA". Developmental Biology 278 (2): 274–88. doi:. PMID 15680349.</ref> It was later discovered that prokaryotic cells, which do not have a nucleus, also contain nucleic acids. The role of RNA in protein synthesis was suspected already in 1939.<ref>Caspersson T, Schultz J (1939). "Pentose nucleotides in the cytoplasm of growing tissues". Nature 143: 602–3. doi:.</ref> Severo Ochoa won the 1959 Nobel Prize in Medicine after he discovered how RNA is synthesized.<ref>Template:Cite web</ref> The sequence of the 77 nucleotides of a yeast tRNA was found by Robert W. Holley in 1965,<ref>Holley RW et al (1965). "Structure of a ribonucleic acid". Science 147 (1664): 1462–65. doi:. PMID 14263761.</ref> winning Holley the 1968 Nobel Prize in Medicine. Carl Woese realised RNA can be catalytic in 1967 and proposed that the earliest forms of life relied on RNA both to carry genetic information and to catalyze biochemical reactions—an RNA world.<ref>Template:Cite web</ref><ref>Szathmáry E (1999). "The origin of the genetic code: amino acids as cofactors in an RNA world". Trends Genet. 15 (6): 223–9. doi:. PMID 10354582.</ref> In 1976, Walter Fiers and his team determined the first complete nucleotide sequence of an RNA virus genome, that of bacteriophage MS2.<ref>Fiers W et al (1976). "Complete nucleotide-sequence of bacteriophage MS2-RNA: primary and secondary structure of replicase gene". Nature 260: 500–7. doi:. PMID 1264203.</ref> In 1990 it was found in petunia that introduced genes can silence similar genes of the plant's own, now known to be a result of RNA interference.<ref>Napoli C, Lemieux C, Jorgensen R (1990). "Introduction of a chimeric chalcone synthase gene into petunia results in reversible co-suppression of homologous genes in trans.". Plant Cell 2 (4): 279–89. doi:. PMID 12354959.</ref><ref>Dafny-Yelin M, Chung SM, Frankman EL, Tzfira T (December 2007). "pSAT RNA interference vectors: a modular series for multiple gene down-regulation in plants". Plant Physiol. 145 (4): 1272–81. doi:. PMID 17766396.</ref> At about the same time, 22 nt long RNAs, now called microRNAs, were found to have a role in the development of C. elegans.<ref>Ruvkun G (2001). "Glimpses of a tiny RNA world". Science 294 (5543): 797–99. doi:. PMID 11679654.</ref> The discovery of gene regulatory RNAs has led to attempts to develop drugs made of RNA, like siRNA, to silence genes.<ref>Fichou Y, Férec C (2006). "The potential of oligonucleotides for therapeutic applications". Trends in Biotechnology 24 (12): 563–70. doi:. PMID 17045686.</ref>
See also
- Genetics
- Molecular biology
- Phosphoramidite
- Quantification of nucleic acids
- RNA Ontology Consortium
- Sequence profiling tool
- RNA extraction
- RNA structure prediction
References
External links
- RNA World website Link collection (structures, sequences, tools, journals)
- Nucleic Acid Database Images of DNA, RNA and complexes.
| ||||||||||||||||||||
