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Messenger RNA

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"MRNA" redirects here. For other uses, seeMRNA (disambiguation).
The "life cycle" of an mRNA in aeukaryoticcell.RNAistranscribedin thenucleus;afterprocessing,it is transported to thecytoplasmandtranslatedby theribosome.Finally, the mRNA is degraded.

Inmolecular biology,messenger ribonucleic acid(mRNA) is a single-strandedmoleculeofRNAthat corresponds to thegenetic sequenceof agene,and is read by aribosomein the process ofsynthesizingaprotein.

mRNA is created during the process oftranscription,where anenzyme(RNA polymerase) converts the gene intoprimary transcriptmRNA (also known aspre-mRNA). This pre-mRNA usually still containsintrons,regions that will not go on to code for the finalamino acid sequence.These are removed in the process ofRNA splicing,leaving onlyexons,regions that will encode the protein. This exon sequence constitutesmature mRNA.Mature mRNA is then read by the ribosome, and the ribosome creates the protein utilizingamino acidscarried bytransfer RNA(tRNA). This process is known astranslation.All of these processes form part of thecentral dogma of molecular biology,which describes the flow of genetic information in a biological system.

As inDNA,genetic information in mRNA is contained in the sequence ofnucleotides,which are arranged intocodonsconsisting of threeribonucleotideseach. Each codon codes for a specificamino acid,except thestop codons,which terminate protein synthesis. The translation of codons into amino acids requires two other types of RNA: transfer RNA, which recognizes the codon and provides the corresponding amino acid, andribosomal RNA(rRNA), the central component of the ribosome's protein-manufacturing machinery.

The concept of mRNA was developed bySydney BrennerandFrancis Crickin 1960 during a conversation withFrançois Jacob.In 1961, mRNA was identified and described independently by one team consisting of Brenner, Jacob, andMatthew Meselson,and another team led byJames Watson.While analyzing the data in preparation for publication, Jacob andJacques Monodcoined the name "messenger RNA".

Synthesis

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RNA polymerase transcribes a DNA strand to form mRNA

The brief existence of an mRNA molecule begins with transcription, and ultimately ends in degradation. During its life, an mRNA molecule may also be processed, edited, and transported prior to translation. Eukaryotic mRNA molecules often require extensive processing and transport, whileprokaryoticmRNA molecules do not. A molecule ofeukaryoticmRNA and the proteins surrounding it are together called amessenger RNP.[citation needed]

Transcription

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Main article:Transcription (genetics)

Transcription is when RNA is copied from DNA. During transcription,RNA polymerasemakes a copy of a gene from the DNA to mRNA as needed. This process differs slightly in eukaryotes and prokaryotes. One notable difference is that prokaryotic RNA polymerase associates with DNA-processing enzymes during transcription so that processing can proceed during transcription. Therefore, this causes the new mRNA strand to become double stranded by producing a complementary strand known as the tRNA strand, which when combined are unable to form structures from base-pairing. Moreover, the template for mRNA is the complementary strand of tRNA, which is identical in sequence to the anticodon sequence that the DNA binds to. The short-lived, unprocessed or partially processed product is termedprecursor mRNA,orpre-mRNA;once completely processed, it is termedmature mRNA.[citation needed]

Uracil substitution for thymine

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mRNA uses uracil (U) instead of thymine (T) in DNA. uracil (U) is the complimentary base to adenine (A) during transcription instead of thymine (T). So when using a template strand of DNA to build RNA, thymine is replaced with uracil. This substitution allows the mRNA to carry the appropriate genetic information from DNA to the ribosome for translation. Regarding the natural history, uracil came first than thymine; evidence suggests that RNA came before DNA in evolution.[1]The RNA World hypothesis proposes that life began with RNA molecules, before the emergence of DNA genomes and coded proteins. In DNA, the evolutionary substitution of thymine for uracil may have increased DNA stability and improved the efficiency of DNA replication.[2][3]

Eukaryotic pre-mRNA processing

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Main article:Post-transcriptional modification
DNA gene is transcribed to pre-mRNA, which is then processed to form a mature mRNA, and then lastly translated by a ribosome to a protein

Processing of mRNA differs greatly amongeukaryotes,bacteria,andarchaea.Non-eukaryotic mRNA is, in essence, mature upon transcription and requires no processing, except in rare cases.[4]Eukaryotic pre-mRNA, however, requires several processing steps before its transport to the cytoplasm and its translation by the ribosome.

Splicing

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Main article:RNA splicing

The extensive processing of eukaryotic pre-mRNA that leads to the mature mRNA is theRNA splicing,a mechanism by whichintronsoroutrons(non-coding regions) are removed andexons(coding regions) are joined.[citation needed]

5' cap addition

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Main article:5' cap
5' cap structure

A5' cap(also termed an RNA cap, an RNA7-methylguanosinecap, or an RNA m7G cap) is a modified guanine nucleotide that has been added to the "front" or5' endof a eukaryotic messenger RNA shortly after the start of transcription. The 5' cap consists of a terminal 7-methylguanosine residue that is linked through a 5'-5'-triphosphate bond to the first transcribed nucleotide. Its presence is critical for recognition by theribosomeand protection fromRNases.[citation needed]

Cap addition is coupled to transcription, and occurs co-transcriptionally, such that each influences the other. Shortly after the start of transcription, the 5' end of the mRNA being synthesized is bound by acap-synthesizing complexassociated withRNA polymerase.Thisenzymaticcomplexcatalyzesthe chemical reactions that are required for mRNA capping. Synthesis proceeds as a multi-stepbiochemicalreaction.[citation needed]

Editing

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In some instances, an mRNA will beedited,changing the nucleotide composition of that mRNA. An example in humans is theapolipoprotein BmRNA, which is edited in some tissues, but not others. The editing creates an early stop codon, which, upon translation, produces a shorter protein.

Polyadenylation

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Main article:Polyadenylation
Polyadenylation

Polyadenylation is the covalent linkage of a polyadenylyl moiety to a messenger RNA molecule. In eukaryotic organisms most messenger RNA (mRNA) molecules are polyadenylated at the 3' end, but recent studies have shown that short stretches of uridine (oligouridylation) are also common.[5]Thepoly(A) tailand the protein bound to it aid in protecting mRNA from degradation by exonucleases. Polyadenylation is also important for transcription termination, export of the mRNA from the nucleus, and translation. mRNA can also be polyadenylated in prokaryotic organisms, where poly(A) tails act to facilitate, rather than impede, exonucleolytic degradation.[citation needed]

Polyadenylation occurs during and/or immediately after transcription of DNA into RNA. After transcription has been terminated, the mRNA chain is cleaved through the action of an endonuclease complex associated with RNA polymerase. After the mRNA has been cleaved, around 250 adenosine residues are added to the free 3' end at the cleavage site. This reaction is catalyzed bypolyadenylate polymerase.Just as inalternative splicing,there can be more than one polyadenylation variant of an mRNA.

Polyadenylation site mutations also occur. The primary RNA transcript of a gene is cleaved at the poly-A addition site, and 100–200 A's are added to the 3' end of the RNA. If this site is altered, an abnormally long and unstable mRNA construct will be formed.

Transport

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Another difference between eukaryotes and prokaryotes is mRNA transport. Because eukaryotic transcription and translation is compartmentally separated, eukaryotic mRNAs must be exported from thenucleusto thecytoplasm—a process that may be regulated by different signaling pathways.[6]Mature mRNAs are recognized by their processed modifications and then exported through thenuclear poreby binding to the cap-binding proteins CBP20 and CBP80,[7]as well as the transcription/export complex (TREX).[8][9]Multiple mRNA export pathways have been identified in eukaryotes.[10]

In spatially complex cells, some mRNAs are transported to particular subcellular destinations. In matureneurons,certain mRNA are transported from thesomatodendrites.One site of mRNA translation is at polyribosomes selectively localized beneath synapses.[11]The mRNA forArc/Arg3.1is induced by synaptic activity and localizes selectively near activesynapsesbased on signals generated byNMDA receptors.[12]Other mRNAs also move into dendrites in response to external stimuli, such asβ-actinmRNA.[13]For export from the nucleus, actin mRNA associates withZBP1[14]and later with40S subunit.The complex is bound by amotor proteinand is transported to the target location (neurite extension) along thecytoskeleton.Eventually ZBP1 isphosphorylatedbySrcin order for translation to be initiated.[15]In developing neurons, mRNAs are also transported into growingaxonsand especially growth cones. Many mRNAs are marked with so-called "zip codes", which target their transport to a specific location.[16][17]mRNAs can also transfer between mammalian cells through structures calledtunneling nanotubes.[18][19]

Translation

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Main article:Translation (biology)
Translation of mRNA to protein

Because prokaryotic mRNA does not need to be processed or transported, translation by theribosomecan begin immediately after the end of transcription. Therefore, it can be said that prokaryotic translation iscoupledto transcription and occursco-transcriptionally.[citation needed]

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 theendoplasmic reticulumby thesignal recognition particle.Therefore, unlike in prokaryotes, eukaryotic translationis notdirectly coupled to transcription. It is even possible in some contexts that reduced mRNA levels are accompanied by increased protein levels, as has been observed for mRNA/protein levels ofEEF1A1inbreast cancer.[20][non-primary source needed]

Structure

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The structure of a mature eukaryotic mRNA. A fully processed mRNA includes a5' cap,5' UTR,coding region,3' UTR,and poly(A) tail.

Coding regions

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Main article:Coding region

Coding regions are composed ofcodons,which are decoded and translated into proteins by the ribosome; in eukaryotes usually into one and in prokaryotes usually into several. Coding regions begin with thestart codonand end with astop codon.In general, the start codon is an AUG triplet and the stop codon is UAG ( "amber" ), UAA ( "ochre" ), or UGA ( "opal" ). The coding regions tend to be stabilised by internal base pairs; this impedes degradation.[21][22]In addition to being protein-coding, portions of coding regions may serve as regulatory sequences in thepre-mRNAasexonic splicing enhancersorexonic splicing silencers.

Untranslated regions

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Main articles:5' UTRand3' UTR
Universal structure of eukaryotic mRNA, showing the structure of the 5' and 3' UTRs.

Untranslated regions (UTRs) are sections of the mRNA before the start codon and after the stop codon that are not translated, termed thefive prime untranslated region(5' UTR) andthree prime untranslated region(3' UTR), respectively. These regions are transcribed with the coding region and thus areexonicas they are present in the mature mRNA. Several roles in gene expression have been attributed to the untranslated regions, including mRNA stability, mRNA localization, andtranslational efficiency.The ability of a UTR to perform these functions depends on the sequence of the UTR and can differ between mRNAs. Genetic variants in 3' UTR have also been implicated in disease susceptibility because of the change in RNA structure and protein translation.[23]

The stability of mRNAs may be controlled by the 5' UTR and/or 3' UTR due to varying affinity for RNA degrading enzymes calledribonucleasesand for ancillary proteins that can promote or inhibit RNA degradation. (See also,C-rich stability element.)

Translational efficiency, including sometimes the complete inhibition of translation, can be controlled by UTRs. Proteins that bind to either the 3' or 5' UTR may affect translation by influencing the ribosome's ability to bind to the mRNA.MicroRNAsbound to the3' UTRalso may affect translational efficiency or mRNA stability.

Cytoplasmic localization of mRNA is thought to be a function of the 3' UTR. Proteins that are needed in a particular region of the cell can also be translated there; in such a case, the 3' UTR may contain sequences that allow the transcript to be localized to this region for translation.

Some of the elements contained in untranslated regions form a characteristicsecondary structurewhen transcribed into RNA. These structural mRNA elements are involved in regulating the mRNA. Some, such as theSECIS element,are targets for proteins to bind. One class of mRNA element, theriboswitches,directly bind small molecules, changing their fold to modify levels of transcription or translation. In these cases, the mRNA regulates itself.

Poly(A) tail

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Main article:Polyadenylation

The 3' poly(A) tail is a long sequence ofadeninenucleotides (often several hundred) added to the3' endof the pre-mRNA. This tail promotes export from the nucleus and translation, and protects the mRNA from degradation.

Monocistronic versus polycistronic mRNA

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See also:Cistron

An mRNA molecule is said to be monocistronic when it contains the genetic information totranslateonly a singleproteinchain (polypeptide). This is the case for most of theeukaryoticmRNAs.[24][25]On the other hand, polycistronic mRNA carries severalopen reading frames(ORFs), each of which is translated into a polypeptide. These polypeptides usually have a related function (they often are the subunits composing a final complex protein) and their coding sequence is grouped and regulated together in a regulatory region, containing apromoterand anoperator.Most of the mRNA found inbacteriaandarchaeais polycistronic,[24]as is the human mitochondrial genome.[26]Dicistronic or bicistronic mRNA encodes only twoproteins.

mRNA circularization

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mRNA circularisation and regulation

In eukaryotes mRNA molecules form circular structures due to an interaction between theeIF4Eandpoly(A)-binding protein,which both bind toeIF4G,forming an mRNA-protein-mRNA bridge.[27]Circularization is thought to promote cycling of ribosomes on the mRNA leading to time-efficient translation, and may also function to ensure only intact mRNA are translated (partially degraded mRNA characteristically have no m7G cap, or no poly-A tail).[28]

Other mechanisms for circularization exist, particularly in virus mRNA.PoliovirusmRNA uses a cloverleaf section towards its 5' end to bind PCBP2, which bindspoly(A)-binding protein,forming the familiar mRNA-protein-mRNA circle.Barley yellow dwarf virushas binding between mRNA segments on its 5' end and 3' end (called kissing stem loops), circularizing the mRNA without any proteins involved.

RNA virus genomes (the + strands of which are translated as mRNA) are also commonly circularized.[29]During genome replication the circularization acts to enhance genome replication speeds, cycling viral RNA-dependent RNA polymerase much the same as the ribosome is hypothesized to cycle.

Degradation

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Different mRNAs within the same cell have distinct lifetimes (stabilities). In bacterial cells, individual mRNAs can survive from seconds to more than an hour. However, the lifetime averages between 1 and 3 minutes, making bacterial mRNA much less stable than eukaryotic mRNA.[30]In mammalian cells, mRNA lifetimes range from several minutes to days.[31]The greater the stability of an mRNA the more protein may be produced from that mRNA. The limited lifetime of mRNA enables a cell to alter protein synthesis rapidly in response to its changing needs. There are many mechanisms that lead to the destruction of an mRNA, some of which are described below.

Prokaryotic mRNA degradation

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Overview of mRNA decay pathways in the different life domains.

In general, in prokaryotes the lifetime of mRNA is much shorter than in eukaryotes. Prokaryotes degrade messages by using a combination of ribonucleases, includingendonucleases,3'exonucleases,and 5' exonucleases. In some instances,small RNA molecules(sRNA) tens to hundreds of nucleotides long can stimulate the degradation of specific mRNAs by base-pairing with complementary sequences and facilitating ribonuclease cleavage byRNase III.It was recently shown that bacteria also have a sort of5' capconsisting of a triphosphate on the5' end.[32]Removal of two of the phosphates leaves a 5' monophosphate, causing the message to be destroyed by the exonuclease RNase J, which degrades 5' to 3'.

Eukaryotic mRNA turnover

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Inside eukaryotic cells, there is a balance between the processes oftranslationand mRNA decay. Messages that are being actively translated are bound byribosomes,theeukaryotic initiation factorseIF-4EandeIF-4G,andpoly(A)-binding protein.eIF-4E and eIF-4G block the decapping enzyme (DCP2), and poly(A)-binding protein blocks theexosome complex,protecting the ends of the message. The balance between translation and decay is reflected in the size and abundance of cytoplasmic structures known asP-bodies.[33]Thepoly(A) tailof the mRNA is shortened by specialized exonucleases that are targeted to specific messenger RNAs by a combination of cis-regulatory sequences on the RNA and trans-acting RNA-binding proteins. Poly(A) tail removal is thought to disrupt the circular structure of the message and destabilize thecap binding complex.The message is then subject to degradation by either theexosome complexor thedecapping complex.In this way, translationally inactive messages can be destroyed quickly, while active messages remain intact. The mechanism by which translation stops and the message is handed-off to decay complexes is not understood in detail.

AU-rich element decay

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The presence ofAU-rich elementsin some mammalian mRNAs tends to destabilize those transcripts through the action of cellular proteins that bind these sequences and stimulatepoly(A)tail removal. Loss of the poly(A) tail is thought to promote mRNA degradation by facilitating attack by both theexosome complex[34]and thedecapping complex.[35]Rapid mRNA degradation viaAU-rich elementsis a critical mechanism for preventing the overproduction of potent cytokines such as tumor necrosis factor (TNF) and granulocyte-macrophage colony stimulating factor (GM-CSF).[36]AU-rich elements also regulate the biosynthesis of proto-oncogenic transcription factors likec-Junandc-Fos.[37]

Nonsense-mediated decay

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Main article:Nonsense-mediated decay

Eukaryotic messages are subject to surveillance bynonsense-mediated decay(NMD), which checks for the presence of premature stop codons (nonsense codons) in the message. These can arise via incomplete splicing,V(D)J recombinationin theadaptive immune system,mutations in DNA, transcription errors,leaky scanningby the ribosome causing aframe shift,and other causes. Detection of a premature stop codon triggers mRNA degradation by 5' decapping, 3'poly(A)tail removal, orendonucleolytic cleavage.[38]

Small interfering RNA (siRNA)

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Main article:siRNA

Inmetazoans,small interfering RNAs(siRNAs) processed byDicerare incorporated into a complex known as theRNA-induced silencing complexor RISC. This complex contains anendonucleasethat cleaves perfectly complementary messages to which the siRNA binds. The resulting mRNA fragments are then destroyed byexonucleases.siRNA is commonly used in laboratories to block the function of genes in cell culture. It is thought to be part of the innate immune system as a defense against double-stranded RNA viruses.[39]

MicroRNA (miRNA)

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Main article:microRNA

MicroRNAs (miRNAs) are small RNAs that typically are partially complementary to sequences in metazoan messenger RNAs.[40][41]Binding of a miRNA to a message can repress translation of that message and accelerate poly(A) tail removal, thereby hastening mRNA degradation. The mechanism of action of miRNAs is the subject of active research.[42][43]

Other decay mechanisms

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There are other ways by which messages can be degraded, includingnon-stop decayand silencing byPiwi-interacting RNA(piRNA), among others.

Applications

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See also:mRNA vaccineandRNA therapeutics

The administration of anucleoside-modified messenger RNAsequence can cause a cell to make a protein, which in turn could directly treat a disease or could function as avaccine;more indirectly the protein could drive an endogenousstem cellto differentiate in a desired way.[44][45]

The primary challenges of RNA therapy center on delivering the RNA to the appropriate cells.[46]Challenges include the fact that naked RNA sequences naturally degrade after preparation; they may trigger the body'simmune systemto attack them as an invader; and they areimpermeableto thecell membrane.[45]Once within the cell, they must then leave the cell's transport mechanism to take action within thecytoplasm,which houses the necessaryribosomes.[44]

Overcoming these challenges, mRNA as a therapeutic was first put forward in 1989 "after the development of a broadly applicable in vitro transfection technique."[47]In the 1990s, mRNA vaccines for personalized cancer have been developed, relying on non-nucleoside modified mRNA. mRNA based therapies continue to be investigated as a method of treatment or therapy for both cancer as well as auto-immune, metabolic, and respiratory inflammatory diseases. Gene editing therapies such asCRISPRmay also benefit from using mRNA to induce cells to make the desiredCasprotein.[48]

Since the 2010s, RNA vaccines and other RNA therapeutics have been considered to be "a new class of drugs".[49]The first mRNA-based vaccines received restricted authorization and were rolled out across the world during theCOVID-19 pandemicbyPfizer–BioNTech COVID-19 vaccineandModerna,for example.[50] The 2023Nobel Prize in Physiology or Medicinewas awarded toKatalin KarikóandDrew Weissmanfor the development of effective mRNA vaccines against COVID-19.[51][52][53]

History

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Several molecular biology studies during the 1950s indicated that RNA played some kind of role in protein synthesis, but that role was not clearly understood. For instance, in one of the earliest reports,Jacques Monodand his team showed that RNA synthesis was necessary for protein synthesis, specifically during the production of the enzymeβ-galactosidasein the bacteriumE. coli.[54]Arthur Pardeealso found similar RNA accumulation in 1954.[55]In 1953,Alfred Hershey,June Dixon, andMartha Chasedescribed a certain cytosine-containing DNA (indicating it was RNA) that disappeared quickly after its synthesis inE. coli.[56]In hindsight, this may have been one of the first observations of the existence of mRNA but it was not recognized at the time as such.[57]

The idea of mRNA was first conceived bySydney BrennerandFrancis Crickon 15 April 1960 atKing's College, Cambridge,whileFrançois Jacobwas telling them about a recent experiment conducted byArthur Pardee,himself, and Monod (the so-called PaJaMo experiment, which did not prove mRNA existed but suggested the possibility of its existence). With Crick's encouragement, Brenner and Jacob immediately set out to test this new hypothesis, and they contactedMatthew Meselsonat theCalifornia Institute of Technologyfor assistance. During the summer of 1960, Brenner, Jacob, and Meselson conducted an experiment in Meselson's laboratory at Caltech which was the first to prove the existence of mRNA. That fall, Jacob and Monod coined the name "messenger RNA" and developed the first theoretical framework to explain its function.[57]

In February 1961,James Watsonrevealed that hisHarvard-based research group had been right behind them with a series of experiments whose results pointed in roughly the same direction. Brenner and the others agreed to Watson's request to delay publication of their research findings. As a result, the Brenner and Watson articles were published simultaneously in the same issue ofNaturein May 1961, while that same month, Jacob and Monod published their theoretical framework for mRNA in theJournal of Molecular Biology.[57]

See also

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Further reading

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Scholiahas a profile formessenger RNA(Q188928).
Wikimedia Commons has media related tomRNA.
Retrieved from "https://en.wikipedia.org/w/index.php?title=Messenger_RNA&oldid=1230702110"