Genetic information stored in DNA is copied into messenger RNA (mRNA) via transcription. The next step, genetic translation, is where the cell’s machinery reads the mRNA instructions to construct a functional protein. This process occurs within the ribosome, which moves along the mRNA strand interpreting three-base sequences called codons. Each codon specifies an amino acid, which the ribosome links together to form a polypeptide chain. To form a protein correctly, the ribosome requires a definitive termination signal to stop assembly.
The Mechanics of Translation Termination
The signal that halts protein synthesis is one of three specific stop codons: UAA, UAG, and UGA. Unlike the 61 other codons, these triplets do not specify an amino acid and are not recognized by a transfer RNA (tRNA) molecule. When the ribosome’s A site encounters one of these sequences, the process shifts from elongation to termination.
The stop codon is instead recognized by specialized proteins called Release Factors (RFs). In human cells, eukaryotic Release Factor 1 (eRF1) recognizes all three stop codons. This protein mimics the shape of a tRNA, allowing it to enter the A site and bind directly to the termination signal. The binding of eRF1 is assisted by eRF3, which uses energy from guanosine triphosphate (GTP) hydrolysis to facilitate termination.
This binding triggers the ultimate chemical reaction of translation termination. The release factor activates a water molecule within the ribosome’s peptidyl transferase center. This water molecule attacks the ester bond linking the completed polypeptide chain to the final tRNA molecule in the P site. This process, known as hydrolysis, cleaves the bond and frees the newly synthesized protein.
Once the polypeptide is released, the remaining molecular complex must dissociate so its components can be recycled. The ribosome splits into its large and small subunits, the mRNA is released, and the release factors depart. This termination ensures the protein is liberated at the exact, predetermined length encoded by the gene.
The Essential Biological Role of Stop Codons
Stop codons guarantee protein fidelity by defining the precise length of every protein produced. Without this unambiguous signal, the ribosome would read the mRNA indefinitely, resulting in excessively long proteins. These elongated polypeptides would be misfolded, non-functional, and potentially toxic, disrupting normal cellular processes.
Stop codons also enforce the boundary of the genetic message, ensuring the integrity of the reading frame. Since codons are read as successive triplets, the termination signal acts as a fixed endpoint. This prevents the ribosome from translating sequences that are not meant to be part of the protein, which is crucial because downstream information is often used for regulatory purposes.
Accurate termination is linked to the cell’s molecular quality control system known as Nonsense-Mediated mRNA Decay (NMD). NMD is a surveillance pathway that detects and rapidly degrades mRNA transcripts that contain a premature stop codon. If a stop signal appears too early in the sequence—typically more than 50 to 55 nucleotides upstream of certain molecular markers—the NMD pathway is activated.
This quality control mechanism prevents the production of short, non-functional protein fragments that might otherwise accumulate. By ensuring that only correctly terminated or full-length mRNAs are translated into stable proteins, the stop codon supports the overall health and function of the cell. The interplay between correct termination and the NMD pathway is a fundamental safeguard of the genome’s integrity.
Consequences of Stop Codon Errors and Disease
Failure of the stop codon system results in significant biological consequences, often manifesting as human disease. The most common error is the creation of a Premature Termination Codon (PTC), also known as a nonsense mutation. This occurs when a single-base change converts an amino acid-specifying codon into one of the three stop codons.
The resulting PTC causes the ribosome to stop translation much earlier than intended, yielding a truncated, incomplete polypeptide chain. Since these shortened proteins usually lack the necessary functional domains, they are typically non-functional or unstable. Nonsense mutations are implicated in approximately 11% of all described human genetic diseases.
Specific disorders, such as Duchenne Muscular Dystrophy (DMD) and Cystic Fibrosis (CF), are frequently caused by PTCs. In DMD, a nonsense mutation in the dystrophin gene leads to a severely shortened, non-functional protein, causing progressive muscle degeneration. For CF, PTCs in the CFTR gene result in a truncated chloride channel protein, impairing its function and leading to disease symptoms.
A different error, a readthrough mutation, occurs when a normal stop codon is mutated into an amino acid-encoding codon or is ignored by the ribosome. This causes translation to continue past the intended endpoint, generating an overly long protein with an extended C-terminus. This extra sequence interferes with proper protein folding, stability, or localization, leading to a dysfunctional product.
Therapeutic approaches are being developed to address PTC-caused diseases using translational read-through inducing drugs (TRIDs), such as Ataluren. These drugs subtly alter the ribosome’s structure, encouraging it to ignore the premature stop codon and insert a near-cognate amino acid. The goal is to allow translation to proceed to the natural stop codon, producing a functional protein that can alleviate disease symptoms.