molecular biology Molecular biology is the branch of biology that seeks to understand the molecular basis of biological activity in and between cells, including biomolecular synthesis, modification, mechanisms, and interactions. The study of chemical and physi ...

, messenger ribonucleic acid (mRNA) is a single-stranded

molecule A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioch ...

RNA Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...

that corresponds to the

genetic sequence A nucleic acid sequence is a succession of bases signified by a series of a set of five different letters that indicate the order of nucleotides forming alleles within a DNA (using GACT) or RNA (GACU) molecule. By convention, sequences are usua ...

of a

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

, and is read by a

ribosome Ribosomes ( ) are macromolecular machines, found within all cells, that perform biological protein synthesis (mRNA translation). Ribosomes link amino acids together in the order specified by the codons of messenger RNA (mRNA) molecules to ...

in the process of synthesizing a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

. mRNA is created during the process of

transcription Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including: Genetics * Transcription (biology), the copying of DNA into RNA, the fir ...

, where an

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

(

RNA polymerase In molecular biology, RNA polymerase (abbreviated RNAP or RNApol), or more specifically DNA-directed/dependent RNA polymerase (DdRP), is an enzyme that synthesizes RNA from a DNA template. Using the enzyme helicase, RNAP locally opens the ...

) converts the gene into

primary transcript A primary transcript is the single-stranded ribonucleic acid (RNA) product synthesized by transcription of DNA, and processed to yield various mature RNA products such as mRNAs, tRNAs, and rRNAs. The primary transcripts designated to be mRNAs a ...

mRNA (also known as

pre-mRNA A primary transcript is the single-stranded ribonucleic acid (RNA) product synthesized by transcription of DNA, and processed to yield various mature RNA products such as mRNAs, tRNAs, and rRNAs. The primary transcripts designated to be mRNAs a ...

). This pre-mRNA usually still contains

introns An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e. a region inside a gene."The notion of the cistron .e., gene. ...

, regions that will not go on to code for the final

amino acid sequence Protein primary structure is the linear sequence of amino acids in a peptide or protein. By convention, the primary structure of a protein is reported starting from the amino-terminal (N) end to the carboxyl-terminal (C) end. Protein biosynthe ...

. These are removed in the process of

RNA splicing RNA splicing is a process in molecular biology where a newly-made precursor messenger RNA (pre-mRNA) transcript is transformed into a mature messenger RNA (mRNA). It works by removing all the introns (non-coding regions of RNA) and ''splicing'' b ...

, leaving only

exons An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...

, regions that will encode the protein. This exon sequence constitutes

mature mRNA Mature messenger RNA, often abbreviated as mature mRNA is a eukaryotic RNA transcript that has been spliced and processed and is ready for translation in the course of protein synthesis. Unlike the eukaryotic RNA immediately after transcription k ...

. Mature mRNA is then read by the ribosome, and, utilising

amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

carried by

transfer RNA Transfer RNA (abbreviated tRNA and formerly referred to as sRNA, for soluble RNA) is an adaptor molecule composed of RNA, typically 76 to 90 nucleotides in length (in eukaryotes), that serves as the physical link between the mRNA and the amino ac ...

(tRNA), the ribosome creates the protein. This process is known as

translation Translation is the communication of the Meaning (linguistic), meaning of a #Source and target languages, source-language text by means of an Dynamic and formal equivalence, equivalent #Source and target languages, target-language text. The ...

. All of these processes form part of the

central dogma of molecular biology The central dogma of molecular biology is an explanation of the flow of genetic information within a biological system. It is often stated as "DNA makes RNA, and RNA makes protein", although this is not its original meaning. It was first stated by ...

, which describes the flow of genetic information in a biological system. As in DNA, genetic information in mRNA is contained in the sequence of

nucleotides Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules w ...

, which are arranged into

codons The genetic code is the set of rules used by living cells to translate information encoded within genetic material ( DNA or RNA sequences of nucleotide triplets, or codons) into proteins. Translation is accomplished by the ribosome, which links ...

consisting of three

ribonucleotide In biochemistry, a ribonucleotide is a nucleotide containing ribose as its pentose component. It is considered a molecular precursor of nucleic acids. Nucleotides are the basic building blocks of DNA and RNA. Ribonucleotides themselves are basic m ...

s each. Each codon codes for a specific

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

, except the

stop codon In molecular biology (specifically protein biosynthesis), a stop codon (or termination codon) is a codon (nucleotide triplet within messenger RNA) that signals the termination of the translation process of the current protein. Most codons in me ...

s, 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, and

ribosomal RNA Ribosomal ribonucleic acid (rRNA) is a type of non-coding RNA which is the primary component of ribosomes, essential to all cells. rRNA is a ribozyme which carries out protein synthesis in ribosomes. Ribosomal RNA is transcribed from ribosomal ...

(rRNA), the central component of the ribosome's protein-manufacturing machinery. The concept of mRNA was developed by

Sydney Brenner Sydney Brenner (13 January 1927 – 5 April 2019) was a South African biologist. In 2002, he shared the Nobel Prize in Physiology or Medicine with H. Robert Horvitz and Sir John E. Sulston. Brenner made significant contributions to work ...

and

Francis Crick Francis Harry Compton Crick (8 June 1916 – 28 July 2004) was an English molecular biologist, biophysicist, and neuroscientist. He, James Watson, Rosalind Franklin, and Maurice Wilkins played crucial roles in deciphering the helical struc ...

in 1960 during a conversation with

François Jacob François Jacob (17 June 1920 – 19 April 2013) was a French biologist who, together with Jacques Monod, originated the idea that control of enzyme levels in all cells occurs through regulation of transcription. He shared the 1965 Nobel Prize i ...

. In 1961, mRNA was identified and described independently by one team consisting of Brenner, Jacob, and

Matthew Meselson Matthew Stanley Meselson (born May 24, 1930) is a geneticist and molecular biologist currently at Harvard University, known for his demonstration, with Franklin Stahl, of semi-conservative DNA replication. After completing his Ph.D. under Linus ...

, and another team led by

James Watson James Dewey Watson (born April 6, 1928) is an American molecular biologist, geneticist, and zoologist. In 1953, he co-authored with Francis Crick the academic paper proposing the double helix structure of the DNA molecule. Watson, Crick and ...

. While analyzing the data in preparation for publication, Jacob and

Jacques Monod Jacques Lucien Monod (February 9, 1910 – May 31, 1976) was a French biochemist who won the Nobel Prize in Physiology or Medicine in 1965, sharing it with François Jacob and André Lwoff "for their discoveries concerning genetic control of en ...

coined the name "messenger RNA".

Synthesis, processing and function

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, while

prokaryotic A prokaryote () is a Unicellular organism, single-celled organism that lacks a cell nucleus, nucleus and other membrane-bound organelles. The word ''prokaryote'' comes from the Greek language, Greek wikt:πρό#Ancient Greek, πρό (, 'before') a ...

mRNA molecules do not. A molecule of

eukaryotic Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...

mRNA and the proteins surrounding it are together called a messenger RNP.

Transcription

Transcription is when RNA is copied from DNA. During transcription,

makes 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 termed ''precursor mRNA'', or ''

''; once completely processed, it is termed ''

''.

Eukaryotic pre-mRNA processing

Processing of mRNA differs greatly among

eukaryote Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...

bacteria Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among ...

, and

archaea Archaea ( ; singular archaeon ) is a domain of single-celled organisms. These microorganisms lack cell nuclei and are therefore prokaryotes. Archaea were initially classified as bacteria, receiving the name archaebacteria (in the Archaebac ...

. Non-eukaryotic mRNA is, in essence, mature upon transcription and requires no processing, except in rare cases. Eukaryotic pre-mRNA, however, requires several processing steps before its transport to the cytoplasm and its translation by the ribosome.

Splicing

The extensive processing of eukaryotic pre-mRNA that leads to the mature mRNA is the

, a mechanism by which

intron An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e. a region inside a gene."The notion of the cistron .e., gene. ...

s or

outron An outron is a nucleotide sequence at the 5' end of the primary transcript of a gene that is removed by a special form of RNA splicing during maturation of the final RNA product. Whereas intron sequences are located inside the gene, outron sequ ...

s (non-coding regions) are removed and

exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequen ...

s (coding regions) are joined.

5' cap addition

A ''5' cap'' (also termed an RNA cap, an RNA

7-methylguanosine 7-Methylguanosine (m7G) is a modified purine nucleoside. It is a methylated version of guanosine and when found in human urine, it may be a biomarker of some types of cancer. In the RNAs, 7-methylguanosine have been used to study and examine the ...

cap, or an RNA m⁷G cap) is a modified guanine nucleotide that has been added to the "front" or

5' end Directionality, in molecular biology and biochemistry, is the end-to-end chemical orientation of a single strand of nucleic acid. In a single strand of DNA or RNA, the chemical convention of naming carbon atoms in the nucleotide pentose-sugar-ri ...

of 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 the

and protection from

RNase Ribonuclease (commonly abbreviated RNase) is a type of nuclease that catalyzes the degradation of RNA into smaller components. Ribonucleases can be divided into endoribonucleases and exoribonucleases, and comprise several sub-classes within the ...

s. 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 a cap-synthesizing complex associated with

. This

enzymatic Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

complex

catalyze Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...

s the chemical reactions that are required for mRNA capping. Synthesis proceeds as a multi-step

biochemical Biochemistry or biological chemistry is the study of chemical processes within and relating to living organisms. A sub-discipline of both chemistry and biology, biochemistry may be divided into three fields: structural biology, enzymology an ...

reaction.

Editing

In some instances, an mRNA will be

edited Editing is the process of selecting and preparing written, photographic, visual, audible, or cinematic material used by a person or an entity to convey a message or information. The editing process can involve correction, condensation, orga ...

, changing the nucleotide composition of that mRNA. An example in humans is the

apolipoprotein B Apolipoprotein B (ApoB) is a protein that in humans is encoded by the gene. Function Apolipoprotein B is the primary apolipoprotein of chylomicrons, VLDL, Lp(a), IDL, and LDL particles (LDL—commonly known as "bad cholesterol" when in refer ...

mRNA, which is edited in some tissues, but not others. The editing creates an early stop codon, which, upon translation, produces a shorter protein.

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. The

poly(A) tail Polyadenylation is the addition of a poly(A) tail to an RNA transcript, typically a messenger RNA (mRNA). The poly(A) tail consists of multiple adenosine monophosphates; in other words, it is a stretch of RNA that has only adenine bases. In euk ...

and 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. 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 by

polyadenylate polymerase In enzymology, a polynucleotide adenylyltransferase () is an enzyme that catalyzes the chemical reaction :ATP + RNA-3'OH \rightleftharpoons pyrophosphate + RNApA-3'OH Thus, the two substrates of this enzyme are ATP and RNA, whereas its two ...

. Just as in

alternative splicing Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be ...

, 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

Another difference between eukaryotes and prokaryotes is mRNA transport. Because eukaryotic transcription and translation is compartmentally separated, eukaryotic mRNAs must be exported from the

nucleus Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to: *Atomic nucleus, the very dense central region of an atom *Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA Nucle ...

to the

cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...

—a process that may be regulated by different signaling pathways. Mature mRNAs are recognized by their processed modifications and then exported through the

nuclear pore A nuclear pore is a part of a large complex of proteins, known as a nuclear pore complex that spans the nuclear envelope, which is the double membrane surrounding the eukaryotic cell nucleus. There are approximately 1,000 nuclear pore complexes ...

by binding to the cap-binding proteins CBP20 and CBP80, as well as the transcription/export complex (TREX). Multiple mRNA export pathways have been identified in eukaryotes. In spatially complex cells, some mRNAs are transported to particular subcellular destinations. In mature

neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...

s, certain mRNA are transported from the

soma Soma may refer to: Businesses and brands * SOMA (architects), a New York–based firm of architects * Soma (company), a company that designs eco-friendly water filtration systems * SOMA Fabrications, a builder of bicycle frames and other bicycle ...

dendrite Dendrites (from Greek δένδρον ''déndron'', "tree"), also dendrons, are branched protoplasmic extensions of a nerve cell that propagate the electrochemical stimulation received from other neural cells to the cell body, or soma, of the n ...

s. One site of mRNA translation is at polyribosomes selectively localized beneath synapses. The mRNA for Arc/Arg3.1 is induced by synaptic activity and localizes selectively near active

synapse In the nervous system, a synapse is a structure that permits a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or to the target effector cell. Synapses are essential to the transmission of nervous impulses from ...

s based on signals generated by

NMDA receptor The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA rece ...

s. Other mRNAs also move into dendrites in response to external stimuli, such as

β-actin Beta-actin (human gene and protein abbreviation ''ACTB''/ACTB) is one of six different actin isoforms which have been identified in humans. This is one of the two nonmuscle cytoskeletal actins. Actins are highly conserved proteins that are invol ...

mRNA. Upon export from the nucleus, actin mRNA associates with

ZBP1 Z-DNA-binding protein 1, also known as DNA-dependent activator of IFN-regulatory factors (DAI) and DLM-1, is a protein that in humans is encoded by the ''ZBP1'' gene. ZBP1 is also an abbreviation for chicken or rat β-actin zipcode-binding protei ...

and the 40S subunit. The complex is bound by a

motor protein Motor proteins are a class of molecular motors that can move along the cytoplasm of cells. They convert chemical energy into mechanical work by the hydrolysis of ATP. Flagellar rotation, however, is powered by a proton pump. Cellular functions ...

and is transported to the target location ( neurite extension) along the

cytoskeleton The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compos ...

. Eventually ZBP1 is

phosphorylated In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, whi ...

by Src in order for translation to be initiated. In developing neurons, mRNAs are also transported into growing

axon An axon (from Greek ἄξων ''áxōn'', axis), or nerve fiber (or nerve fibre: see spelling differences), is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action po ...

s and especially growth cones. Many mRNAs are marked with so-called "zip codes," which target their transport to a specific location. mRNAs can also transfer between mammalian cells through structures called

tunneling nanotube A tunneling nanotube (TNT) or membrane nanotube is a term that has been applied to protrusions that extend from the plasma membrane which enable different animal cells to touch over long distances, sometimes over 100 μm between T cells. Two ty ...

Translation

Because prokaryotic mRNA does not need to be processed or transported, translation by the

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 The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...

by the

signal recognition particle The signal recognition particle (SRP) is an abundant, cytosolic, universally conserved ribonucleoprotein (protein-RNA complex) that recognizes and targets specific proteins to the endoplasmic reticulum in eukaryotes and the plasma membrane ...

. Therefore, unlike in prokaryotes, eukaryotic translation ''is not'' directly 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 of

EEF1A1 Elongation factor 1-alpha 1 (eEF1a1) is a translation elongation protein, expressed across eukaryotes. In humans, it is encoded by the ''EEF1A1'' gene. This gene encodes an isoform of the alpha subunit of the elongation factor-1 complex, which i ...

breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a re ...

Structure

Coding regions

Coding regions are composed of

, 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 the

start codon The start codon is the first codon of a messenger RNA (mRNA) transcript translated by a ribosome. The start codon always codes for methionine in eukaryotes and Archaea and a N-formylmethionine (fMet) in bacteria, mitochondria and plastids. The ...

and end with a

. 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. In addition to being protein-coding, portions of coding regions may serve as regulatory sequences in the

exonic splicing enhancer In molecular biology, an exonic splicing enhancer (ESE) is a DNA sequence motif consisting of 6 bases within an exon that directs, or enhances, accurate splicing of heterogeneous nuclear RNA ( hnRNA) or pre-mRNA into messenger RNA (mRNA). Intr ...

s or

exonic splicing silencer An exonic splicing silencer (ESS) is a short region (usually 4-18 nucleotides) of an exon and is a cis-regulatory element. A set of 103 hexanucleotides known as FAS-hex3 has been shown to be abundant in ESS regions. ESSs inhibit or silence splicing ...

Untranslated regions

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 The 5′ untranslated region (also known as 5′ UTR, leader sequence, transcript leader, or leader RNA) is the region of a messenger RNA (mRNA) that is directly upstream from the initiation codon. This region is important for the regulation of t ...

(5' UTR) and

three prime untranslated region In molecular genetics, the three prime untranslated region (3′-UTR) is the section of messenger RNA (mRNA) that immediately follows the translation termination codon. The 3′-UTR often contains regulatory regions that post-transcriptionally ...

(3' UTR), respectively. These regions are transcribed with the coding region and thus are

ic 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. 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. The stability of mRNAs may be controlled by the 5' UTR and/or 3' UTR due to varying affinity for RNA degrading enzymes called

ribonuclease Ribonuclease (commonly abbreviated RNase) is a type of nuclease that catalyzes the degradation of RNA into smaller components. Ribonucleases can be divided into endoribonucleases and exoribonucleases, and comprise several sub-classes within the ...

s and 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.

MicroRNA MicroRNA (miRNA) are small, single-stranded, non-coding RNA molecules containing 21 to 23 nucleotides. Found in plants, animals and some viruses, miRNAs are involved in RNA silencing and post-transcriptional regulation of gene expression. miRN ...

s bound to the

3' UTR In molecular genetics, the three prime untranslated region (3′-UTR) is the section of messenger RNA (mRNA) that immediately follows the translation termination codon. The 3′-UTR often contains regulatory regions that post-transcriptionally ...

also 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 characteristic

secondary structure Protein secondary structure is the three dimensional conformational isomerism, form of ''local segments'' of proteins. The two most common Protein structure#Secondary structure, secondary structural elements are alpha helix, alpha helices and beta ...

when transcribed into RNA. These structural mRNA elements are involved in regulating the mRNA. Some, such as the

SECIS element In biology, the SECIS element (SECIS: ''selenocysteine insertion sequence'') is an RNA element around 60 nucleotides in length that adopts a stem-loop structure. This structural motif (pattern of nucleotides) directs the cell to translate UGA co ...

, are targets for proteins to bind. One class of mRNA element, the

riboswitch In molecular biology, a riboswitch is a regulatory segment of a messenger RNA molecule that binds a small molecule, resulting in a change in production of the proteins encoded by the mRNA. Thus, an mRNA that contains a riboswitch is directly invo ...

es, directly bind small molecules, changing their fold to modify levels of transcription or translation. In these cases, the mRNA regulates itself.

Poly(A) tail

The 3' poly(A) tail is a long sequence of

adenine Adenine () ( symbol A or Ade) is a nucleobase (a purine derivative). It is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The three others are guanine, cytosine and thymine. Its derivati ...

nucleotides (often several hundred) added to the

3' end Directionality, in molecular biology and biochemistry, is the end-to-end chemical orientation of a single strand of nucleic acid. In a single strand of DNA or RNA, the chemical convention of naming carbon atoms in the nucleotide pentose-sugar-ri ...

of the pre-mRNA. This tail promotes export from the nucleus and translation, and protects the mRNA from degradation.

Monocistronic versus polycistronic mRNA

An mRNA molecule is said to be monocistronic when it contains the genetic information to

translate Translation is the communication of the meaning of a source-language text by means of an equivalent target-language text. The English language draws a terminological distinction (which does not exist in every language) between ''transl ...

only a single

chain (polypeptide). This is the case for most of the

mRNAs. On the other hand, polycistronic mRNA carries several

open reading frame In molecular biology, open reading frames (ORFs) are defined as spans of DNA sequence between the start and stop codons. Usually, this is considered within a studied region of a prokaryotic DNA sequence, where only one of the six possible readin ...

s (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 a promoter and an operator. Most of the mRNA found in

and

is polycistronic, as is the human mitochondrial genome. Dicistronic or bicistronic mRNA encodes only two

mRNA circularization

In eukaryotes mRNA molecules form circular structures due to an interaction between the

eIF4E Eukaryotic translation initiation factor 4E, also known as eIF4E, is a protein that in humans is encoded by the ''EIF4E'' gene. Structure and function Most eukaryotic cellular mRNAs are blocked at their 5'-ends with the 7-methyl-guanosine fi ...

and

poly(A)-binding protein Poly(A)-binding protein (PAB or PABP) is an RNA-binding protein which triggers the binding of eukaryotic initiation factor 4 complex (eIF4G) directly to the poly(A) tail of mRNA which is 200-250 nucleotides long. The poly(A) tail is located on the ...

, which both bind to

eIF4G Eukaryotic translation initiation factor 4 G (eIF4G) is a protein involved in eukaryotic translation initiation and is a component of the eIF4F cap-binding complex. Orthologs of eIF4G have been studied in multiple species, including humans, yeast ...

, forming an mRNA-protein-mRNA bridge. 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). Other mechanisms for circularization exist, particularly in virus mRNA.

Poliovirus A poliovirus, the causative agent of polio (also known as poliomyelitis), is a serotype of the species ''Enterovirus C'', in the family of ''Picornaviridae''. There are three poliovirus serotypes: types 1, 2, and 3. Poliovirus is composed of an ...

mRNA uses a cloverleaf section towards its 5' end to bind PCBP2, which binds

, forming the familiar mRNA-protein-mRNA circle.

Barley yellow dwarf virus Barley yellow dwarf (BYD) is a plant disease caused by the ''barley yellow dwarf virus'' (BYDV), and is the most widely distributed viral disease of cereals. It affects the economically important crop species barley, oats, wheat, maize, tritical ...

has 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. 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

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. In mammalian cells, mRNA lifetimes range from several minutes to days. 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

In general, in prokaryotes the lifetime of mRNA is much shorter than in eukaryotes. Prokaryotes degrade messages by using a combination of ribonucleases, including

endonuclease Endonucleases are enzymes that cleave the phosphodiester bond within a polynucleotide chain. Some, such as deoxyribonuclease I, cut DNA relatively nonspecifically (without regard to sequence), while many, typically called restriction endonucleases ...

s, 3'

exonuclease Exonucleases are enzymes that work by cleaving nucleotides one at a time from the end (exo) of a polynucleotide chain. A hydrolyzing reaction that breaks phosphodiester bonds at either the 3′ or the 5′ end occurs. Its close relative is the ...

s, 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 by

RNase III Ribonuclease III (RNase III or RNase C)(BREND3.1.26.3 is a type of ribonuclease that recognizes dsRNA and cleaves it at specific targeted locations to transform them into mature RNAs. These enzymes are a group of endoribonucleases that are chara ...

. It was recently shown that bacteria also have a sort of

5' cap In molecular biology, the five-prime cap (5′ cap) is a specially altered nucleotide on the 5′ end of some primary transcripts such as precursor messenger RNA. This process, known as mRNA capping, is highly regulated and vital in the creation o ...

consisting of a triphosphate on the

. 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

Inside eukaryotic cells, there is a balance between the processes of

and mRNA decay. Messages that are being actively translated are bound by

s, the

eukaryotic initiation factor Eukaryotic initiation factors (eIFs) are Protein, proteins or Protein complex, protein complexes involved in the initiation phase of eukaryotic translation. These proteins help stabilize the formation of ribosomal preinitiation complexes around the ...

eIF-4E Eukaryotic initiation factors (eIFs) are proteins or protein complexes involved in the initiation phase of eukaryotic translation. These proteins help stabilize the formation of ribosomal preinitiation complexes around the start codon and are an im ...

and

eIF-4G Eukaryotic initiation factors (eIFs) are proteins or protein complexes involved in the initiation phase of eukaryotic translation. These proteins help stabilize the formation of ribosomal preinitiation complexes around the start codon and are an im ...

, and

. eIF-4E and eIF-4G block the decapping enzyme (

DCP2 mRNA-decapping enzyme 2 is a protein that in humans is encoded by the ''DCP2'' gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ...

), and poly(A)-binding protein blocks the

exosome complex The exosome complex (or PM/Scl complex, often just called the exosome) is a multi-protein intracellular complex capable of degrading various types of RNA (ribonucleic acid) molecules. Exosome complexes are found in both eukaryotic cells and a ...

, protecting the ends of the message. The balance between translation and decay is reflected in the size and abundance of cytoplasmic structures known as

P-bodies P-bodies, or processing bodies are distinct foci formed by phase separation within the cytoplasm of the eukaryotic cell consisting of many enzymes involved in mRNA turnover. P-bodies are highly conserved structures and have been observed in soma ...

. The

of 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 the cap binding complex. The message is then subject to degradation by either the

or the

decapping complex The mRNA decapping complex is a protein complex in eukaryotic cells responsible for removal of the 5' cap. The active enzyme of the decapping complex is the bilobed Nudix family enzyme Dcp2, which hydrolyzes 5' cap and releases 7mGDP and a 5'-m ...

. 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

The presence of

AU-rich element Adenylate-uridylate-rich elements (AU-rich elements; AREs) are found in the 3' untranslated region (UTR) of many messenger RNAs (mRNAs) that code for proto-oncogenes, nuclear transcription factors, and cytokines. AREs are one of the most common de ...

s in some mammalian mRNAs tends to destabilize those transcripts through the action of cellular proteins that bind these sequences and stimulate

poly(A) Polyadenylation is the addition of a poly(A) tail to an RNA transcript, typically a messenger RNA (mRNA). The poly(A) tail consists of multiple adenosine monophosphates; in other words, it is a stretch of RNA that has only adenine bases. In euka ...

tail removal. Loss of the poly(A) tail is thought to promote mRNA degradation by facilitating attack by both the

and the

. Rapid mRNA degradation via

s is a critical mechanism for preventing the overproduction of potent cytokines such as tumor necrosis factor (TNF) and granulocyte-macrophage colony stimulating factor (GM-CSF). AU-rich elements also regulate the biosynthesis of proto-oncogenic transcription factors like

c-Jun Transcription factor Jun is a protein that in humans is encoded by the ''JUN'' gene. c-Jun, in combination with protein c-Fos, forms the AP-1 early response transcription factor. It was first identified as the Fos-binding protein p39 and only lat ...

and

c-Fos Protein c-Fos is a proto-oncogene that is the human homolog of the retroviral oncogene v-fos. It is encoded in humans by the ''FOS'' gene. It was first discovered in rat fibroblasts as the transforming gene of the FBJ MSV (Finkel–Biskis–Jinkin ...

Nonsense-mediated decay

Eukaryotic messages are subject to surveillance by

nonsense-mediated decay Nonsense-mediated mRNA decay (NMD) is a surveillance pathway that exists in all eukaryotes. Its main function is to reduce errors in gene expression by eliminating mRNA transcripts that contain premature stop codons. Translation of these aberrant ...

(NMD), which checks for the presence of premature stop codons (nonsense codons) in the message. These can arise via incomplete splicing,

V(D)J recombination V(D)J recombination is the mechanism of somatic recombination that occurs only in developing lymphocytes during the early stages of T and B cell maturation. It results in the highly diverse repertoire of antibodies/immunoglobulins and T cell rece ...

in the

adaptive immune system The adaptive immune system, also known as the acquired immune system, is a subsystem of the immune system that is composed of specialized, systemic cells and processes that eliminate pathogens or prevent their growth. The acquired immune system ...

, mutations in DNA, transcription errors,

leaky scanning Leaky scanning is a mechanism used during the initiation phase of eukaryotic translation that enables regulation of gene expression. During initiation, the small 40S ribosomal subunit (as a 43S PIC) "scans" or moves in a 5' --> 3' direction along ...

by the ribosome causing a

frame shift Ribosomal frameshifting, also known as translational frameshifting or translational recoding, is a biological phenomenon that occurs during translation that results in the production of multiple, unique proteins from a single mRNA. The process can ...

, and other causes. Detection of a premature stop codon triggers mRNA degradation by 5' decapping, 3'

tail removal, or endonucleolytic cleavage.

Small interfering RNA (siRNA)

metazoan Animals are multicellular, eukaryotic organisms in the biological kingdom Animalia. With few exceptions, animals Heterotroph, consume organic material, Cellular respiration#Aerobic respiration, breathe oxygen, are Motility, able to move, ca ...

small interfering RNA Small interfering RNA (siRNA), sometimes known as short interfering RNA or silencing RNA, is a class of double-stranded RNA at first non-coding RNA molecules, typically 20-24 (normally 21) base pairs in length, similar to miRNA, and operating wi ...

s (siRNAs) processed by

Dicer Dicer, also known as endoribonuclease Dicer or helicase with RNase motif, is an enzyme that in humans is encoded by the gene. Being part of the RNase III family, Dicer cleaves double-stranded RNA (dsRNA) and pre-microRNA (pre-miRNA) into short d ...

are incorporated into a complex known as the

RNA-induced silencing complex The RNA-induced silencing complex, or RISC, is a multiprotein complex, specifically a ribonucleoprotein, which functions in gene silencing via a variety of pathways at the transcriptional and translational levels. Using single-stranded RNA (ssRNA) ...

or RISC. This complex contains an

that cleaves perfectly complementary messages to which the siRNA binds. The resulting mRNA fragments are then destroyed by

s. 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.

MicroRNA (miRNA)

MicroRNAs (miRNAs) are small RNAs that typically are partially complementary to sequences in metazoan messenger RNAs. 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.

Other decay mechanisms

There are other ways by which messages can be degraded, including

non-stop decay Non-stop decay (NSD) is a cellular mechanism of mRNA surveillance to detect mRNA molecules lacking a stop codon and prevent these mRNAs from translation. The non-stop decay pathway releases ribosomes that have reached the far 3' end of an mRNA and ...

and silencing by

Piwi-interacting RNA Piwi-interacting RNA (piRNA) is the largest class of small non-coding RNA molecules expressed in animal cells. piRNAs form RNA-protein complexes through interactions with piwi-subfamily Argonaute proteins. These piRNA complexes are mostly involved ...

(piRNA), among others.

Applications

The administration of a

nucleoside-modified messenger RNA A nucleoside-modified messenger RNA (modRNA) is a synthetic messenger RNA (mRNA) in which some nucleosides are replaced by other naturally modified nucleosides or by synthetic nucleoside analogues. modRNA is used to induce the production of a des ...

sequence can cause a cell to make a protein, which in turn could directly treat a disease or could function as a

vaccine A vaccine is a biological Dosage form, preparation that provides active acquired immunity to a particular infectious disease, infectious or cancer, malignant disease. The safety and effectiveness of vaccines has been widely studied and verifie ...

; more indirectly the protein could drive an endogenous

stem cell In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type o ...

to differentiate in a desired way. The primary challenges of RNA therapy center on delivering the RNA to the appropriate cells. Challenges include the fact that naked RNA sequences naturally degrade after preparation; they may trigger the body's

immune system The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...

to attack them as an invader; and they are impermeable to the

cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...

. Once within the cell, they must then leave the cell's transport mechanism to take action within the

, which houses the necessary

ribosomes Ribosomes ( ) are macromolecular machines, found within all cells, that perform biological protein synthesis (mRNA translation). Ribosomes link amino acids together in the order specified by the codons of messenger RNA (mRNA) molecules to f ...

. Overcoming these challenges, mRNA as a therapeutic was first put forward in 1989 "after the development of a broadly applicable in vitro transfection technique." 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 as

CRISPR CRISPR () (an acronym for clustered regularly interspaced short palindromic repeats) is a family of DNA sequences found in the genomes of prokaryotic organisms such as bacteria and archaea. These sequences are derived from DNA fragments of bacte ...

may also benefit from using mRNA to induce cells to make the desired Cas protein. Since the 2010s, RNA vaccines and other RNA therapeutics have been considered to be "a new class of drugs." The first mRNA-based vaccines received restricted authorization and were rolled out across the world during the

COVID-19 pandemic The COVID-19 pandemic, also known as the coronavirus pandemic, is an ongoing global pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The novel virus was first identif ...

Pfizer–BioNTech COVID-19 vaccine The Pfizer–BioNTech COVID-19 vaccine ( INN: tozinameran), sold under the brand name Comirnaty, is an mRNA-based COVID-19 vaccine developed by the German biotechnology company BioNTech. For its development, BioNTech collaborated with Amer ...

and

Moderna Moderna, Inc. ( ) is an American pharmaceutical and biotechnology company based in Cambridge, Massachusetts that focuses on RNA therapeutics, primarily mRNA vaccines. These vaccines use a copy of a molecule called messenger RNA (mRNA) to produ ...

, for example.

History

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,

and his team showed that RNA synthesis was necessary for protein synthesis, specifically during the production of the enzyme

β-galactosidase β-Galactosidase (EC 3.2.1.23, lactase, beta-gal or β-gal; systematic name β-D-galactoside galactohydrolase), is a glycoside hydrolase enzyme that catalyzes hydrolysis of terminal non-reducing β-D-galactose residues in β-D-galactosides. β ...

in the bacterium ''

E. coli ''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus ''Escher ...

''.

Arthur Pardee Arthur Beck Pardee (July 13, 1921 – February 24, 2019) was an American biochemist. One biographical portrait begins "Among the titans of science, Arthur Pardee is especially intriguing." There is hardly a field of molecular biology that is not ...

also found similar RNA accumulation in 1954''.'' In 1953,

Alfred Hershey Alfred Day Hershey (December 4, 1908 – May 22, 1997) was an American Nobel Prize–winning bacteriologist and geneticist. He was born in Owosso, Michigan and received his B.S. in chemistry at Michigan State University in 1930 and his Ph.D. ...

, June Dixon, and

Martha Chase Martha Cowles Chase (November 30, 1927 – August 8, 2003), also known as Martha C. Epstein, was an American geneticist who in 1952, with Alfred Hershey, experimentally helped to confirm that DNA rather than protein is the genetic material o ...

described a certain cytosine-containing DNA (indicating it was RNA) that disappeared quickly after its synthesis in ''E. coli''. 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. The idea of mRNA was first conceived by

and

on 15 April 1960 at

King's College, Cambridge King's College is a constituent college of the University of Cambridge. Formally The King's College of Our Lady and Saint Nicholas in Cambridge, the college lies beside the River Cam and faces out onto King's Parade in the centre of the city ...

, while

was telling them about a recent experiment conducted by

, 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 contacted

at the

California Institute of Technology The California Institute of Technology (branded as Caltech or CIT)The university itself only spells its short form as "Caltech"; the institution considers other spellings such a"Cal Tech" and "CalTech" incorrect. The institute is also occasional ...

for 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. In February 1961,

revealed that his

Harvard Harvard University is a private Ivy League research university in Cambridge, Massachusetts. Founded in 1636 as Harvard College and named for its first benefactor, the Puritan clergyman John Harvard, it is the oldest institution of higher le ...

-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 of ''

Nature Nature, in the broadest sense, is the physics, physical world or universe. "Nature" can refer to the phenomenon, phenomena of the physical world, and also to life in general. The study of nature is a large, if not the only, part of science. ...

'' in May 1961, while that same month, Jacob and Monod published their theoretical framework for mRNA in the ''

Journal of Molecular Biology The ''Journal of Molecular Biology'' is a biweekly peer-reviewed scientific journal covering all aspects of molecular biology. It was established in 1959 and is published by Elsevier. The editor-in-chief is Peter Wright ( The Scripps Research In ...

''.

References

External links

RNAi Atlas
a database of RNAi libraries and their target analysis results
miRSearch
: Tool for finding microRNAs that target mRNA
How mRNA is coded?
YouTube video
What is mRNA?
theconversation.com {{Gene expression RNA Gene expression Protein biosynthesis Molecular genetics Spliceosome RNA splicing Life sciences industry