A readthrough mutation is a genetic alteration that impacts protein production. Normally, genetic instructions include signals that tell the cellular machinery where to stop building a protein. A readthrough mutation causes this machinery to ignore that stop signal, creating an abnormally long protein. This altered length can significantly affect protein function.
The Molecular Mechanism
Protein synthesis, or translation, involves ribosomes reading messenger RNA (mRNA) sequences. These mRNA sequences are made up of codons, three-nucleotide units that specify which amino acid to add to a growing protein chain. Among these, three codons—UAA, UAG, and UGA—act as “stop” signals, signaling the end of protein assembly.
When a ribosome encounters one of these stop codons, specialized protein factors bind to the ribosome, releasing the newly formed protein. This ensures proteins are the correct length and sequence. However, in a readthrough mutation, the stop codon is bypassed, allowing the ribosome to add amino acids beyond the termination point.
This bypassing can occur if a transfer RNA (tRNA) molecule, which carries a specific amino acid, incorrectly recognizes the stop codon. Instead of translation terminating, an amino acid is inserted, and the ribosome proceeds to translate the sequence following the stop codon. The result is an elongated protein with additional amino acids at its C-terminus.
Functional Consequences
The addition of extra amino acids due to a readthrough mutation can alter the resulting protein. Proteins must fold into three-dimensional shapes to function effectively. An elongated protein might not fold correctly, leading to a misfolded or unstable structure. Improper folding can hinder the protein’s interaction with other molecules or its cellular tasks.
Beyond structural changes, the elongated protein may exhibit altered stability, becoming more susceptible to degradation by cellular quality control mechanisms. Cells identify and remove faulty proteins, so an abnormally long protein might be targeted for destruction, reducing functional protein availability. The extra amino acids can also affect the protein’s localization within the cell, potentially misdirecting it or preventing it from reaching its destination.
These changes in structure, stability, and localization can lead to a loss of the protein’s intended function or, in some cases, a modified or even new function. Such alterations can disrupt normal cellular processes, as many cellular activities depend on the coordinated actions of numerous proteins. Cellular consequences can range from subtle inefficiencies to severe functional impairments, depending on the protein’s role.
Biological Significance and Implications
Readthrough mutations are significant in normal biological processes and human health. In some biological systems, certain viruses use programmed readthrough as a regulated mechanism to produce multiple protein variants from a single gene. This genetic economy enables viruses to encode more proteins within a limited sequence, contributing to adaptability and life cycle.
However, when readthrough occurs unintentionally in genes, it can contribute to various diseases. Many genetic disorders are caused by mutations that introduce a premature stop codon, leading to a truncated, often non-functional protein. Readthrough of such premature stop codons can sometimes restore the production of a full-length protein, which, even if altered, might regain some function. This principle is being explored therapeutically for certain genetic conditions.
Conversely, unregulated readthrough of naturally occurring stop codons can also be detrimental, leading to elongated, dysfunctional proteins that can disrupt cellular pathways. This can result in protein aggregation or interference with normal protein interactions, contributing to various disorders. Understanding the factors that influence readthrough and its effects is important for basic biological research and new therapeutic strategies.