Nonsense-mediated decay

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Nonsense-mediated mRNA decay (NMD) is a surveillance pathway that exists in all eukaryotes. Its main function is to reduce errors in gene expression by eliminating mRNA transcripts that contain premature stop codons.[1] If these aberrant mRNA transcripts were translated, the result would be deleterious gain-of-function or dominant-negative activity of the resulting proteins.[2] While many of the proteins involved in NMD are not conserved between species, in Saccharomyces cerevisiae (yeast), there are three main factors in NMD: UPF1, UPF2 and UPF3 (UPF3A and UPF3B in humans), that make up the conserved core of the NMD pathway.[3] All three of these factors are trans-acting elements called up-frameshift (UPF) proteins. In mammals, UPF2 and UPF3 are part of the exon-exon junction complex (EJC) bound to mRNA after splicing along with other proteins, eIF4AIII, MLN51, and the Y14/MAGOH heterodimer, which also function in NMD. UPF1 phosphorylation is controlled by the proteins SMG-1, SMG-5, SMG-6 and SMG-7.

The process of detecting aberrant transcripts occurs during translation of the mRNA. A popular model for the detection of aberrant transcripts in mammals suggests that during the first round of translation, the ribosome removes the exon-exon junction complexes bound to the mRNA after splicing occurs. If after this first round of translation, any of these proteins remain bound to the mRNA, NMD is activated. Exon-exon junction complexes located downstream of a stop codon are not removed from the transcript because the ribosome is released before reaching them. Termination of translation leads to the assembly of a complex composed of UPF1, SMG1 and the release factors, eRF1 and eRF2, on the mRNA. If an EJC is left on the mRNA because the transcript contains a premature stop codon, then UPF1 comes into contact with UPF2 and UPF3, triggering the phosphorylation of UPF1. The phosphorylated UPF1 then interacts with SMG-5, SMG-6 and SMG-7, which promote the dephosphorylation of UPF1. SMG-7 is thought to be the terminating effector in NMD, as it accumulates in P-bodies, which are cytoplasmic sites for mRNA decay. In both yeast and human cells, the major pathway for mRNA decay is initiated by the removal of the 5’ cap followed by degradation by XRN1, an exoribonuclease enzyme. The other pathway by which mRNA is degraded is by deadenylation from 3’-5'. Nonsense-mediated decay is a new and important aspect to human genetics. It has the possibility to not only limit the translation of abnormal proteins, but it can occasionally cause detrimental effects in specific genetic mutations [4]

Mutations[edit]

Although nonsense-mediated mRNA decay reduces nonsense codons, mutations can occur that lead to various health problems and diseases in humans. A dominant-negative or deleterious gain-of-function mutation can occur if premature terminating (nonsense) codons are translated. NMD is becoming increasingly evident in the way it modifies phenotypic consequences because of the broad way it controls gene expression. For instance, the blood disorder, Beta thalassemia is inherited and caused by mutations within the upstream of the β-globin gene.[5] An individual carrying only one affected allele will have no or extremely low levels of the mutant β-globin mRNA. An even more sever form of the disease can occur called thalassemia intermedia or ‘inclusion body’ thalassemia. Instead of decreased mRNA levels, a mutant transcript produces truncated β chains, which in turn leads to a clinical phenotype in the heterozygote.[6] Nonsense-mediated decay mutations can also contribute to Marfan syndrome. This disorder is caused by mutations in the fibrillin 1 (FBN1) gene and is resulted from a dominant negative interaction between mutant and wild-type fibrillin-1 gene.[7]

See also[edit]

References[edit]

  1. ^ Baker, K. E.; Parker, R. (2004). "Nonsense-mediated mRNA decay: Terminating erroneous gene expression". Current Opinion in Cell Biology 16 (3): 293–299. doi:10.1016/j.ceb.2004.03.003. PMID 15145354.  edit
  2. ^ Chang, Y. F.; Imam, J. S.; Wilkinson, M. F. (2007). "The nonsense-mediated decay RNA surveillance pathway". Annual Review of Biochemistry 76: 51–74. doi:10.1146/annurev.biochem.76.050106.093909. ISSN 0066-4154. PMID 17352659.  edit
  3. ^ Behm-Ansmant, I.; Izaurralde, E. (2006). "Quality control of gene expression: A stepwise assembly pathway for the surveillance complex that triggers nonsense-mediated mRNA decay". Genes & Development 20 (4): 391–398. doi:10.1101/gad.1407606. PMID 16481468.  edit
  4. ^ Holbrook, Jill (2004). "Nonsense-mediated decay approaches the clinic". Nature Genetics 36: 801–808. doi:10.1038/ng1403. 
  5. ^ Frischmeyer, Dietz, Pamela, Harry (1999). "Nonsense-Mediated mRNA Decay in Health and Disease". Oxford Journals 8 (10): 1893–1900. doi:10.1093/hmg/8.10.1893. 
  6. ^ Frischmeyer, Dietz, Pamela, Harry (1999). "Nonsense-Mediated mRNA Decay in Health and Disease". Oxford Journals 8 (10): 1893–1900. doi:10.1093/hmg/8.10.1893. 
  7. ^ Frischmeyer, Dietz, Pamela, Harry (1999). "Nonsense-Mediated mRNA Decay in Health and Disease". Oxford Journals 8 (10): 1893–1900. doi:10.1093/hmg/8.10.1893. 

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