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'.

Reader's Guide

Messenger RNA is central to the central dogma of molecular biology, which describes the flow of genetic information in a biological system. It is synthesized during transcription, where RNA polymerase binds to a promoter sequence on DNA and synthesizes a complementary RNA strand. In eukaryotes, transcription occurs within the cell nucleus, and the initial product is pre-mRNA, which must undergo extensive processing including 5' capping, splicing to remove non-coding introns, and 3' polyadenylation to become mature mRNA. The 5' cap is a modified guanine nucleotide added shortly after transcription start, critical for ribosome recognition and protection from RNases. Polyadenylation adds around 200–250 adenosine residues to the 3' end, aiding in protection from degradation, transcription termination, nuclear export, and translation. Mature mRNA is then exported from the nucleus to the cytoplasm for translation. In prokaryotes, transcription occurs in the cytoplasm and ribosomes can attach to the nascent mRNA strand and begin translation while transcription is still in progress. The discovery of mRNA resolved how genetic information is transferred from DNA to protein, and its characterization in 1961 by Brenner, Jacob, Meselson, and Gros was a landmark in molecular biology.

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'.
• Eukaryotic pre-mRNA usually still contains introns, which are removed in the process of RNA splicing, leaving only exons that will encode the protein.
• The 5' cap consists of a terminal 7-methylguanosine residue linked through a 5'-5'-triphosphate bond to the first transcribed nucleotide.

The Ribosome as Cellular Factory

Translation is the process by which the ribosome creates a protein utilizing amino acids carried by transfer RNA (tRNA). The ribosome reads the mature mRNA, which contains codons consisting of three ribonucleotides each. Each codon codes for a specific amino acid, except 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.

Decoding the Genetic Code

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 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.

The Elongation Dance: Sites, Bonds, and Energy

Once translation is underway, the ribosome maintains two key tRNA binding positions: the aminoacyl site (A) and the peptidyl/exit site (P/E). Relative to the mRNA, these sites are arranged in the order E-P-A along the 5' to 3' axis, reflecting the ribosome's forward movement toward the 3' end. A charged tRNA enters the A site, where its anticodon pairs with the exposed codon. A peptide bond then forms between the incoming amino acid and the polypeptide already attached to the tRNA in the P/E site, transferring the growing chain to the A-site tRNA. Translocation follows, powered by GTP hydrolysis carried out by the translocase EEF2, which shifts the ribosome one codon downstream. The now-uncharged tRNA exits, and a new charged tRNA enters the A site to repeat the cycle. Energy demands are substantial: translating a protein of n amino acids requires 4n minus 1 high-energy phosphate bonds. Prokaryotic cells translate at rates of up to 17–21 residues per second, considerably faster than eukaryotic rates of 6–9.

Getting Started: Initiation and the 5' Cap

The 5' cap (also termed an RNA cap, an RNA 7-methylguanosine cap, or an RNA m7G 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 that 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. 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.