Messenger RNA

Lore & Background

The concept of mRNA was first conceived by Sydney Brenner and Francis Crick in 1960 during a conversation with François Jacob. In May 1961, messenger RNA was experimentally characterized in two back-to-back Nature papers: one by Brenner, Jacob, and Meselson, and one by Gros and colleagues (including Watson). While analyzing the data in preparation for publication, Jacob and Jacques Monod coined the term "messenger RNA". mRNA is created during transcription, where RNA polymerase converts a gene into primary transcript mRNA (pre-mRNA). This pre-mRNA usually still contains introns, which are removed in RNA splicing, leaving only exons that constitute mature mRNA. Mature mRNA is then read by the ribosome, which creates the protein using amino acids carried by transfer RNA (tRNA) in a process called translation. Eukaryotic mRNA molecules often require extensive processing and transport, while prokaryotic mRNA molecules do not. In eukaryotes, transcription occurs within the cell nucleus. The initial product of transcription is not functional mRNA but is termed precursor mRNA or pre-mRNA. This pre-mRNA must undergo extensive processing (including 5' capping, splicing to remove non-coding introns, and 3' polyadenylation) to become mature mRNA. Once processed, the mature mRNA is exported from the nucleus to the cytoplasm for translation. In prokaryotes, transcription occurs in the cytoplasm. Because prokaryotes lack a membrane-bound nucleus, ribosomes can attach to the nascent mRNA strand and begin translation while transcription is still in progress. As in DNA, genetic information in mRNA is contained in the sequence of nucleotides, which are arranged into codons consisting of three ribonucleotides each. Each codon codes for a specific amino acid, except the stop 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, and ribosomal RNA (rRNA), the central component of the ribosome's protein-manufacturing machinery. Whereas DNA contains thymine (T), RNA contains uracil (U). During the process of transcription, the enzyme RNA polymerase incorporates uracil opposite adenine bases located on the DNA template strand. Therefore, the resulting RNA transcript contains uracil in the positions where the coding DNA strand contains thymine. Structurally, uracil–adenine (U–A) base pairs closely resemble thymine–adenine (T–A) base pairs, which ensures that the genetic information carried by the sequence is faithfully preserved. A frequently cited explanation for the presence of thymine in DNA involves the necessity of genome maintenance. Because cytosine can spontaneously deaminate to form uracil, DNA repair systems recognize uracil as a form of damage. The utilization of thymine as a standard base allows the cell to distinguish legitimate bases from errors, thereby maintaining uracil as a specific signal for repair.

Reader's Guide

Messenger RNA is central to the central dogma of molecular biology, serving as the intermediary that carries genetic information from DNA to ribosomes for protein synthesis. Its discovery in 1960–1961 by Brenner, Crick, Jacob, Monod, and others revolutionized understanding of gene expression. The molecule's structure—single-stranded, with uracil replacing thymine—allows it to be transcribed from DNA and translated into proteins. Key processing steps in eukaryotes, such as splicing, capping, and polyadenylation, ensure mRNA stability, export, and efficient translation. The ability to edit mRNA, as seen in apolipoprotein B and A-to-I editing, adds regulatory complexity. mRNA's role in protein synthesis makes it fundamental to all life, and its properties have been harnessed in biotechnology, including vaccine development. The distinction between prokaryotic and eukaryotic mRNA processing highlights evolutionary adaptations in gene regulation. In some instances, an mRNA molecule is edited, which changes the nucleotide composition of the transcript. A prominent example in humans involves the apolipoprotein B mRNA. In certain tissues, RNA editing of this transcript creates a premature stop codon, which results in the production of a shorter protein variant. Another well studied mechanism is A-to-I (adenosine-to-inosine) editing. This reaction is catalyzed by ADAR enzymes (adenosine deaminase acting on RNA) and typically occurs within double-stranded RNA regions. A-to-I editing may occur in both coding sequences and untranslated regions. Through these modifications, the process can affect protein recoding, RNA structure, and gene regulation. 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 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. 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—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 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 neurons, certain mRNA are transported from the soma to dendrites. 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 synapses based on signals generated by NMDA receptors. Other mRNAs also move into dendrites in response to external stimuli, such as β-actin mRNA. For export from the nucleus, actin mRNA associates with ZBP1 and later with 40S subunit. The complex is bound by a motor protein and is transported to the target location (neurite extension) along the cytoskeleton. Eventually ZBP1 is phosphorylated by Src in order for translation to be initiated. In developing neurons, mRNAs are also transported into growing axons 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 nanotubes.

Did You Know?

• The concept of mRNA was first conceived by Sydney Brenner and Francis Crick in 1960 during a conversation with François Jacob.
• In May 1961, messenger RNA was experimentally characterized in two back-to-back Nature papers: one by Brenner, Jacob, and Meselson, and one by Gros and colleagues (including Watson).
• While analyzing the data in preparation for publication, Jacob and Jacques Monod coined the term 'messenger RNA'.
• A prominent example of mRNA editing in humans involves the apolipoprotein B mRNA, where editing creates a premature stop codon resulting in a shorter protein variant.
• mRNAs can transfer between mammalian cells through structures called tunneling nanotubes.