(Redirected from MRNA)
The "life cycle" of an 'mRNA' in a eukaryotic cell. RNA is
transcribed in the
nucleus; once completely processed, it is transported to the
cytoplasm and
translated by the
ribosome. At the end of its life, the mRNA is degraded.
'Messenger Ribonucleic Acid' ('mRNA') is a molecule of
RNA encoding a chemical "blueprint" for a
protein product. mRNA is
transcribed from a
DNA template, and carries coding information to the sites of
protein synthesis: the
ribosomes. Here, the nucleic acid polymer is
translated into a polymer of
amino acids: a protein. In mRNA as in DNA, genetic information is encoded in the sequence of four
nucleotides arranged into
codons of three bases each. Each codon encodes for a specific
amino acid, except the
stop codons that terminate protein synthesis. This process requires two other types of RNA:
Transfer RNA ('tRNA') mediates recognition of the codon and provides the corresponding amino acid, while
Ribosomal RNA ('rRNA') is the central component of the ribosome's protein manufacturing machinery.
mRNA "life cycle"
The brief life 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 molecules do not.
Transcription
Main articles: Transcription (genetics)
During transcription,
RNA polymerase makes a copy of a gene from the DNA to mRNA as needed. This process is similar in eukaryotes and prokaryotes. One notable difference, however, is that eukaryotic RNA polymerase associates with mRNA processing enzymes during transcription so that processing can proceed quickly after the start of transcription. The short-lived, unprocessed or partially processed, product is termed ''
pre-mRNA''; once completely processed, it is termed ''
mature mRNA''.
Eukaryotic pre-mRNA processing
Main articles: Post transcriptional modification
Processing of mRNA differs greatly between
eukaryotes,
bacteria and
archea. Non-eukaryotic mRNA is essentially mature upon transcription and requires no processing, except in rare cases. Eukaryotic pre-mRNA, however, requires extensive processing.
Splicing
Main articles: Splicing (genetics)
Splicing is the process by which pre-mRNA is modified to remove certain stretches of non-coding sequences called
introns; the stretches that remain include protein-coding sequences and are called
exons. Sometimes pre-mRNA messages may be spliced in several different ways, allowing a single gene to encode multiple proteins. This process is called
alternative splicing. Splicing is usually performed by an RNA-protein complex called the
spliceosome, but some RNA molecules are also capable of catalyzing their own splicing (''see
ribozymes'').
5' cap addition
Main articles: 5' cap
The ''5' cap'' is a modified guanine nucleotide added to the "front" (
5' end) of the pre-mRNA using a 5',5-Triphosphate linkage. This modification is critical for recognition and proper attachment of mRNA to the ribosome, as well as protection from 5' exonucleases. It may also be important for other essential processes, such as splicing and transport.
Editing
In some instances, an mRNA will be
edited, changing the nucleotide composition of that mRNA. An example in humans is the
apolipoprotein B 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
Main articles: 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. The
poly(A) tail 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 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. The cleavage site is characterized by the presence of the base sequence AAUAAA near the cleavage site. After the mRNA has been cleaved, 80 to 250 adenosine residues are added to the free 3' end at the cleavage site. This reaction is catalyzed by polyadenylate polymerase.
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 to the
cytoplasm. Mature mRNAs are recognized by their processed modifications and then exported through the
nuclear pore.
Translation
Main articles: Translation (genetics)
Because prokaryotic mRNA does not need to be processed or transported, 'translation' by the
ribosome can begin immediately after the end of transcription. Therefore, it can be said that prokaryotic translation is ''coupled'' to transcription and occurs ''co-transcriptionally''.
Eukaryotic mRNA that has been processed and transported to the cytoplasm (i.e. mature mRNA) can then be translated by the ribosome. Translation may occur at
ribosomes free-floating in the cytoplasm, or directed to the
endoplasmic reticulum by the
signal recognition particle. Therefore, unlike prokaryotes, eukaryotic translation ''is not'' directly coupled to transcription.
Degradation
After a certain amount of time, the message is degraded by
RNases into its component nucleotides. The limited longevity of mRNA enables a cell to alter protein synthesis rapidly in response to its changing needs.
Different mRNAs within the same cell have distinct lifetimes. In bacterial cells, individual mRNAs can survive from seconds to more than an hour; 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 transcript. The presence of AU-rich motifs in some mammalian mRNAs tends to destabilize those transcripts through the action of cellular proteins that bind these motifs. Rapid mRNA degradation via AU-rich motifs 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).
[1]
mRNA structure
5' cap
Main articles: 5' cap
A ''5' cap'', also termed an RNA cap, an RNA 7-methylguanosine cap or an RNA m
7G cap, is a modified guanine nucleotide that has been added to the "front" or
5' end of a eukaryotic messenger RNA shortly after the start of transcription. The 5' cap consists of a terminal 7-methylguanosine residue which is linked through a 5'-5'-triphosphate bond to the first transcribed nucleotide. Its presence is critical for recognition by the
ribosome and protection from
RNases.
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
RNA polymerase. This
enzymatic complex
catalyzes the chemical reactions that are required for mRNA capping. Synthesis proceeds as a multi-step
biochemical reaction.
First, the triphosphate at the
5' end of the newly synthesized RNA is cleaved. The enzyme phosphohydrolase cleaves the gamma phosphodiester bonds while leaving the alpha and beta
phosphates. Second, the enzyme guanylyltransferase transfers a
guanine and its alpha phosphate onto the beta phosphate of the 5' end of the mRNA producing a 5'-5'-triphosphate linkage. Third, the
nitrogen-7 (N-7) position of the newly added guanine is methylated (guaninemethylation) by the enzyme guanine-7-methyltransferase. Finally, 2'-O-methyltransferase methylates the 2' position of the ribose sugar. This methyl group provides extra stability to the RNA due to the protection from phosphoester cleavage by nucleophilic attack of the neighbor hydrogen. After the 5' end has been capped, it is released from the cap-synthesizing complex and is subsequently bound by a cap-binding complex associated with RNA polymerase.
Coding regions
Main articles: Coding region
Coding regions are composed of
codons, which are decoded and translated into protein by the ribosome. Coding regions begin with the
start codon and end with the one of three possible
stop codons. In addition to protein-coding, portions of coding regions may also serve as regulatory sequences in the
pre-mRNA as
exonic splicing enhancers or
exonic splicing silencers.
Monocistronic versus polycistronic mRNA
An mRNA molecule is said to be
monocistronic when it contains the genetic information to
translate only a single
protein. This is the case for most of the
eukaryotic mRNAs
[2]. On the other hand,
polycistronic mRNA carries the information of several proteins, which are translated into single proteins. Most of the mRNA found in
bacteria and
archea are polycistronic
. Dicistronic is the term used to describe a mRNA that encodes only two
proteins.
Untranslated regions
Main articles: 5' UTR,
3' UTR
Untranslated regions (UTRs) are sections of the RNA before the start codon and after the stop codon that are not translated, termed the
five prime untranslated region (5' UTR) and
three prime untranslated region (3' UTR), respectively. These regions are transcribed as part of the same transcript as the coding region. 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.
The stability of mRNAs may be controlled by the 5' UTR and/or 3' UTR due to varying affinity for RNA degrading enzymes called
ribonucleases and for ancillary proteins that can promote or inhibit RNA degradation.
Translational efficiency, and even inhibition of translation altogether, can be mediated by UTRs. Proteins that bind to either the 3' or 5' UTR may affect translation by interfering with the ribosome's ability to bind to the mRNA.
MicroRNAs also bind to the
3' UTR and may affect stability or efficiency.
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 actually 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 when transcribed into RNA. These structural mRNA elements are involved in regulating the mRNA. Some, such as the
SECIS element, are targets for proteins to bind. One class of mRNA element, the
riboswitches, directly bind small molecules, changing their fold to modify levels of transcription or translation. In these cases, the mRNA regulates itself.
3' poly(A) tail
Main articles: Polyadenylation
The 3' poly(A) tail is a long sequence of
adenine nucleotides (often several hundred) added to the "tail" or
3' end of the pre-mRNA through the action of an enzyme, polyadenylate polymerase. In higher eukaryotes, the poly(A) tail is added onto transcripts that contain a specific sequence, the AAUAAA signal. The importance of the AAUAAA signal is demonstrated by a mutation in the human alpha 2-globin gene that changes the original sequence AATAAA into AATAAG, which can lead to hemoglobin deficiencies.
[3]
Anti-sense mRNA
During transcription, double stranded DNA produces mRNA from the ''sense'' strand; the other, complementary, strand of DNA is termed ''anti-sense''. Anti-sense mRNA is an RNA complementary in sequence to one or more mRNAs. In some organisms, the presence of an anti-sense mRNA can inhibit
gene expression by base-pairing with the specific mRNAs. In
biochemical research, this effect has been used to study gene function, by simply shutting down the studied gene by adding its anti-sense mRNA transcript. Such studies have been done on the
worm ''
Caenorhabditis elegans'' and the
bacterium ''
Escherichia coli''. This plays a part in
RNA interference and RNA transcription.
See also
★
RNA
★
Micro-RNA
★
Non-coding RNA
★
DNA
★
Hubert Chantrenne
References
1. Shaw, G. and Kamen, R. "A conserved AU sequence from the 3' untranslated region of GM-CSF mRNA mediates selective mRNA degradation." Cell. 1986 Aug 29;46(5):659-67. PMID: 3488815 CELL
2.
3.
External links
★
Life of mRNA Flash animation
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