Nonsense-mediated decay

As Nonsense - mediated mRNA decay (NMD ) is a control mechanism in eukaryotic cells called that detects unwanted ( premature) termination codon in the mRNA and prevents its expression as a truncated proteins.

Principle

In a premature stop codon in the open reading frame of an mRNA of the nonsense - mediated mRNA decay is initiated. Premature stop codons arise as a result of gene mutations ( nonsense mutations ), alternative splicing or faulty or errors in the transcription. The resulting truncated proteins can lead to a loss of function, but in rarer cases, such as in the removal of regulatory protein domains, can also lead to a profit function.

In the transcription of the information of DNA is transferred to the mRNA, however, is present as a first pre-mRNA, that is, as a precursor, which is still to be processed. Here are removed among other things, in the course of splicing introns and exons joined together. The exon - exon boundaries remain within the mRNA by protein complexes are labeled (English Exon Junction Complex). These protein complexes are normally removed during the first round of translation. Only then the translation is used at the regular stop codon to a stop and the termination factors are activated. However, where a premature stop codon in the open reading frame of the mRNA, the translation is already there to a standstill. Also in this case, the termination factors are activated. However, since this is a premature stop codon at which translation has come to a halt, is usually ( in 5' -3 'direction considered ) behind another exon junction complex, can interact with the termination factors. This has the result that, inter alia, decapping enzymes are activated, which remove the 5'- cap of the mRNA, resulting in a rapid degradation of the mRNA by 5'-3 ' exonucleases result. However, the requirement for an interaction of the termination factors at the exon junction complexes that premature stop codon at least 50-55 base-pairs (as viewed in the 5' -3 'direction ) in front of the last exon- binding is located. Therefore, the mechanism of NMD does not take place:

• When the pre-mRNA introns has no
• When the premature stop codon in exon past (or in the last 50 base pairs of the penultimate ) is

The nonsense - mediated mRNA decay consists of three conserved parts, UPF1, UPF2 and UPF3 (or UPF3A and UPF3B in humans). These three factors are the trans -activation response elements, which are called up frameshift protein. In mammals UPF2 and UPF3 part of the exon junction complex ( EJC ) after splicing, in combination with the proteins eIF4AIII, MLN51 and the Y14/MAGOH heterodimer. The EJC protein complex remains bound in a premature stop codon in the mRNA. UPF1 is characterized as part of the Terminationskomplexes with SMG -1, eRF1 and eRF2 in binding to the mRNA in the vicinity of the UPF2 and UPF3, whereby the phosphorylation of the UPF1 can occur. The phosphorylated UPF3 binds SMG -5, SMG -6 and SMG -7, which initiates the dephosphorylation of UPF3. Then, a defective degradation of the mRNA takes place in the P-bodies in the cytosol, starting with the removal of the cap structure by the exoribonuclease XNR1.

Parallel to the NMD through the nonsense-mediated translational repression ( Nmtr ), the nonsense -associated alternative splicing (NAS ) and the nonsense-mediated transcriptional gene silencing ( NMTGS ) from.

The NMD is highly conserved phylogenetically and has been found in all studied eukaryotes. In unmodified cells, NMD is thought to play a role in the quality control of mechanisms that increase the diversity of gene expression ( eg alternative splicing or V (D) J recombination as an example of somatic recombination). The NMD has great medical importance, the effect can be positive as well as negative effects on the body especially in modulating the severity of various diseases.

In the case of inherited or acquired as part of a disease gene mutations of NMD is the elimination of mRNA transcripts that would encode truncated proteins. Heterozygous carriers of nonsense mutations will be protected from possible toxic effect of truncated proteins. However, it is also nonsense mRNAs eliminated, at least in part have led to the synthesis of functional proteins, which may have negative effects on the organism.

β -thalassemia

An example of the " mitigating " effect of NMD, the autosomal recessive β -thalassemia dar. For the form of this disease, there are three different options:

Duchenne muscular dystrophy

The Duchenne muscular dystrophy ( DMD) is an X -linked recessive hereditary degenerative muscle disease. Accordingly, almost exclusively men suffer because the additional Y chromosome has no dominance function. A mutation in the dystrophin gene causes a frameshift with a nonsense mutation in the corresponding mRNA as a result. Through the NMD results in degradation of the mRNA, resulting in a total loss of dystrophin protein as a result. Thus, no result but possibly shortened but still functional or partially functional proteins.

An important role of NMD also in cancers, where there is often an accumulation of mutations in the diseased cells.