The nosense-mediated mRNA decay ( eng. Nonsense- mediated mRNA decay, NMD ) is one of several cytoplasmic cell systems that controls the quality of mRNA . On the NMD pathway, mRNA is cleaved, containing stop codons in the wrong places (in the open reading frame ) and, therefore, incorrectly spliced . Thus, NMD protects the cell from the synthesis of truncated proteins , which can be dangerous for the cell [1] . By regulating gene expression, NMD is involved in such cellular processes as growth and proliferation , response to stress or viral invasion, regulates the work of acquired immunity , neuron activity and behavior [2] .
Nonsense-mediated decay is of major clinical importance. First, it alleviates the symptoms of many hereditary diseases , preventing the defective proteins from synthesizing. Secondly, mutations of various proteins that regulate NMD can lead to serious disturbances in the development of the nervous system ; in addition, they are associated with the development of specific tumors [2] .
It is possible that nonsense-mediated decay played an extremely important role in the evolution of eukaryotes, allowing them to master new genes formed during DNA rearrangements, as it made it possible to choose only those mRNAs that can give rise to full-length proteins for translation [1] .
Content
Study History
NMD was originally described in Saccharomyces cerevisiae yeast and Caenorhabditis elegans nematodes ; however, this pathway has now been found in all eukaryotic cells studied, and the key proteins of this mechanism are conserved from yeast to humans . For a long time, it was believed that NMD acts only as a protective mechanism that prevents the synthesis of defective proteins, but later it was found that its substrate can be a significant proportion of normal wild-type mRNA. Therefore, nonsense-mediated decay should be considered not only as a protective mechanism, but also as a fundamental mechanism of post-transcriptional regulation of gene expression in eukaryotes [2] .
General Principle
Nonsense-mediated degradation is activated during the transport of mRNA from the nucleus to the cytosol . When the 5'-end of the mRNA leaves the nuclear pore , the ribosome binds to it and starts the protein translation. At the same time, the ( English Exon junction complex, EJC ), associated with the mRNA at each site through which the splicing was performed, are displaced by the moving ribosome. Since normally the stop codon is at the end of the last exon, there should be no EJC on the mRNA after it. The mRNA, in which this is the case, is released into the cytosol, where their translation is completed. If, on the contrary, the ribosome stops at a premature stop codon, then the mRNA continues to carry the EJC. Such mRNAs are subject to immediate degradation. Thus, nonsense-mediated degradation provides control of mRNA at their exit from the nucleus [3] .
Clinical value
Nonsense-mediated decay can mitigate the manifestations of many hereditary diseases in individuals carrying one normal allele and one mutated allele containing a nonsense mutation . Such mutations , which change the structure of the protein , make up about 15% of all point mutations associated with hereditary diseases. Transcripts encoding aberrant proteins will be destroyed along the NMD pathway, and they will not have a toxic effect on the cell [4] . In addition, the effectiveness of NMD can be directly related to the severity of symptoms and the outcome of the disease [2] .
As noted above, mutations of various proteins that regulate NMD can be associated with impaired development of the nervous system and a number of types of cancer [2] .
Notes
- ↑ 1 2 Alberts et al., 2013 , p. 593.
- 2 1 2 3 4 5 He F. , Jacobson A. Nonsense-Mediated mRNA Decay: Degradation of Defective Transcripts. (English) // Annual review of genetics. - 2015. - Vol. 49. - P. 339-366. - DOI : 10.1146 / annurev-genet-112414-054639 . - PMID 26436458 .
- ↑ Alberts et al., 2013 , p. 593-594.
- ↑ Alberts et al., 2013 , p. 595.
Literature
- B. Alberts, A. Johnson, D. Lewis, et al. Molecular cell biology / Trans. from English A. N. Dyakonova, A. V. Dyuba and A. A. Svetlov. Ed. E.S. Shilova, B.P. Kopnin, M.A. Lagarkova, D.V. Kuprash. - M. — Izhevsk: SIC “Regular and chaotic dynamics”, 2013. - T. 2. - p. 1213. - 1052 p. - ISBN 978-5-4344-0137-1 .