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Why inactive mRNA becomes the focus of cells: How does NMD monitor gene expression?
In the world of cells, gene expression is a crucial process in which every step must be carefully monitored. Nonsense-mediated mRNA decay (NMD) serves as a surveillance mechanism that reduces errors in gene expression, especially those mRNAs containing premature stop codons. By eliminating these abnormal mRNAs, NMD not only protects the normal operation of cells, but also may affect the overall biological function.
NMD is a surveillance pathway present in all eukaryotes, whose main function is to eliminate mRNA transcripts containing premature stop codons.
NMD was first described in human cells and yeast in 1979, demonstrating its widespread conservation and important role in biological evolution. The discovery of unexpectedly low concentrations of transcripts of genes carrying nonsense mutations in cells prompted the investigation of this mechanism. Nonsense mutations result in shortened proteins and can be potentially harmful whether or not they are functional.
The main components of NMD include proteins such as UPF1, UPF2 and UPF3, which have a conserved core structure in yeast. These transfer acceleration factors play a key role in the monitoring process. Especially during the translation stage, when translation is performed for the first time, the ribosome removes many exon-exon junction complexes (EJCs) bound to the mRNA. If these junction complexes remain during this translation process, In mRNA, NMD is activated.
Once abnormal transcripts are detected, NMD kicks in to prevent these erroneous mRNA transcripts from being translated into proteins.
Correct mRNA transcription is crucial in gene expression, but with the advancement of science, more and more research is being done on NMD. NMD not only restricts the translation of abnormal proteins, but also plays an important role in regulating normal gene functions, such as synaptic plasticity of neurons, which may affect adult behavior.
After studying the efficiency of NMD, it was found that it was affected by multiple molecular characteristics, including the EJC model, the position of PTC (premature termination codon), the length of exon, etc. These factors can all affect the ability of NMD to recognize and degrade erroneous mRNAs. For example, if the PTC is located downstream of the last EJC, the efficiency of NMD will often be reduced. This study implies that it is necessary to understand these molecular rules when designing studies targeting specific genes.
The study indicates that the efficiency of NMD may also be affected when the PTC is close to the start codon or is at a longer distance from the normal stop codon.
However, mutations remain a potential threat to health, and the emergence of nonsense mutations may lead to a variety of health problems. Take β-thalassemia as an example. This genetic disease is caused by a mutation in the β-globin gene. The mRNA in the mutant's body usually has lower levels or is not even translated.
NMD has also been implicated in several applications in immunology, with regard to how to regulate antigens generated by frameshift mutations. In cancer cells, these frameshift mutations generate abnormal proteins that may be seen as neoantigens. However, these mutations often result in mRNA degradation by NMD before it can be translated into protein.
Understanding NMD is equally important in gene editing techniques such as CRISPR-Cas9. If the targeted gene mutation results in a premature stop codon and enters the NMD pathway, the gene will be rapidly degraded. On the contrary, if the mutation is located in a way that avoids NMD, the resulting mutant mRNA may still retain some function, thus affecting the complete inactivation of the gene.
In short, NMD plays a key role in the regulation of gene expression. Its research not only helps us understand the basic regulatory mechanisms of genes and life processes, but also provides new ideas for the diagnosis and treatment of genetic diseases. In the future, this mechanism may have greater potential in drug development and gene editing. Can we further understand the mysteries of this mechanism to address the challenges facing human health?
