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Did you know? How does NMD drive cells to repair genetic errors? Uncover its mystery!
Nonsense-mediated mRNA decay (NMD) is a surveillance pathway present in all eukaryotes. Its main function is to reduce defects in gene expression by eliminating mRNA transcripts containing premature stop codons. mistake. This process is critical to reducing the production of harmful proteins that result from translating these aberrant mRNAs. The discovery of NMD dates back to 1979, when it was described in eukaryotic cells and yeast almost simultaneously, indicating that this mechanism is widely conserved in evolution and of important biological significance.
This mechanism eliminates unexpectedly low concentrations of mRNA caused by early stop codons transcribed on alleles.
The operating mechanism of monitoring pathways
The process of NMD mainly involves several key proteins. In the yeast Saccharomyces cerevisiae, the main three factors include UPF1, UPF2 and UPF3 (the corresponding ones in humans are UPF3A and UPF3B). These factors form the conserved core of the NMD pathway. When mRNA is spliced, UPF2 and UPF3 become part of the spliced exon-exon junction complex (EJC) and bind to the mRNA.
The detection process of NMD occurs during the translation of mRNA. After the first round of translation, if the EJC protein is still bound to the mRNA, NMD will be activated.
Molecular rules affecting NMD efficiency
The efficiency of the NMD pathway is affected by a variety of molecular characteristics. In research on NMD, some core molecular rules have been discovered, such as the EJC model, initiation proximity effect, exon length and the distance from early stop codon to normal stop codon, etc., which will affect the response of NMD to abnormal mRNA. Recognition and degradation efficiency.
For example, if the early stop codon is located upstream of the last EJC, NMD will generally be triggered, but if it is located downstream, NMD will usually be less efficient.
Association between genetic mutations and NMD
Although the existence of NMD can effectively reduce incorrect codons, mutations may still cause health problems. For example, beta thalassemia is caused by mutations upstream of the beta-globin gene. Individuals with only one affected allele typically exhibit very low levels of mutant β-globin mRNA.
These mutations can also lead to the emergence of Marfan syndrome, which is due to mutations in the fibrillin 1 gene, and its phenotypic effects are closely related to NMD.
The role of NMD in immune response
In addition, NMD is also involved in the regulation of immunogenic frame-shift mutation-derived antigens. Frame-shift mutations lead to the production of abnormal proteins, which are often recognized by the immune system as neoantigens. However, these mutations may also lead to activation of NMD, thereby reducing the expression of these abnormal mRNAs.
Applications in scientific research
The importance of NMD in gene regulation makes it an emerging area of research. By studying NMD, scientists can find the causes of certain genetic diseases and further explore dosage compensation mechanisms in mammals.
For example, mutations in the POMC gene have been found to be related to many metabolic processes and affect the regulation of body weight.
Finally, the rules of NMD are also critical when designing CRISPR-Cas9 experiments, as these experiments may lead to frame-shift mutations and the generation of early stop codons.
As we gain a deeper understanding of the mechanisms of NMD and its biological significance, this field may reveal more mysteries of gene expression regulation. Have you ever wondered whether NMD can become a new direction in the treatment of genetic mutation-related diseases?
