Nonsense-mediated mRNA decay

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As nonsense-mediated decay ( NMD ), a control mechanism is in eukaryotic cells referred to the undesired (premature) termination codons in the mRNA recognizes and their expression as truncated proteins prevented.

principle

In the event of a premature stop codon in the open reading frame of an mRNA, the nonsense-mediated mRNA decay is triggered. Premature stop codons arise as a result of gene mutations (nonsense mutations, trunking mutations ), alternative or faulty splicing or errors in transcription . The resulting shortened proteins can lead to a loss of function, but in rarer cases, e.g. B. in the removal of regulatory protein domains , also lead to a gain in functionality.

During the transcription, the information in the DNA is transferred to the mRNA, which, however, is first present as pre-mRNA, i.e. as a preliminary stage that still has to be processed . Among other things, the introns are removed and the exons joined together during the splicing process . The exon-exon boundaries within the mRNA remain marked by protein complexes (English exon junction complex ). These protein complexes are usually removed during the first round of translation . Only then does translation come to a standstill at the regular stop codon and the termination factors are activated. However, if there is a premature stop codon in the open reading frame of the mRNA, translation comes to a standstill there. The termination factors are also activated in this case. However, since it is a premature stop codon at which translation has come to a standstill, there is usually an exon junction complex behind it (viewed in the 5'-3 'direction) with which the termination factors can interact . As a result, among other things, decapping enzymes are activated, which remove the 5 'cap of the mRNA, which results in rapid degradation of the mRNA by 5'-3' exonucleases . However, the prerequisite for an interaction of the termination factors with the exon junction complexes is that the premature stop codon is at least 50-55 base pairs (viewed in the 5'-3 'direction) before the last exon-exon binding. Therefore, the mechanism of NMD does not take place:

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

The nonsense-mediated mRNA decay consists of three conserved parts, UPF1 , UPF2 and UPF3 (or UPF3A and UPF3B in humans). These three factors are called up-frameshift proteins . In mammals, UPF2 and UPF3 are part of the exon junction complex (EJC) after the splicing process, in conjunction with the proteins eIF4AIII, MLN51 and the Y14 / MAGOH heterodimer. The EJC protein complex remains bound to the mRNA in the event of a premature stop codon. As a result, UPF1, as part of the termination complex with SMG-1, eRF1 and eRF2, comes close to UPF2 and UPF3 when it binds to the mRNA, which means that UPF1 can be phosphorylated . The phosphorylated UPF3 binds SMG-5, SMG-6 and SMG-7, which initiates the dephosphorylation of the UPF3. The defective mRNA is then broken down in P bodies in the cytosol , beginning with the removal of the cap structure by the exoribonuclease XNR1.

The nonsense-mediated translational repression (NMTR), the nonsense-associated alternative splicing (NAS) and the nonsense-mediated transcriptional gene silencing (NMTGS) run parallel to the NMD .

The NMD is phylogenetically highly conserved and has so far been found in every examined eukaryotic organism. In unchanged cells, NMD probably plays a role in the quality control of mechanisms that increase the diversity of gene expression (e.g. alternative splicing or V (D) J recombination as an example of somatic recombination). The NMD is of great medical importance, especially when it comes to modulating the severity of various clinical pictures, whereby the effect on the organism can be positive but also negative.

In the case of genetic mutations that are inherited or acquired as part of a disease, the NMD serves to eliminate mRNA transcripts that would code for shortened proteins. Heterozygous carriers of nonsense mutations are thus protected from any toxic effects of shortened proteins. However, nonsense mRNAs are also eliminated that would have led to the synthesis of at least partially functional proteins, which can have negative effects on the organism.

β-thalassemia

Nonsense mutations in the 1st exon or in the 2nd exon activate NMD, nonsense mutations in the last exon and 50 bp before that do not.

An example of the "damage-limiting" effect of NMD is the autosomal recessive inherited β- thalassemia . There are three different possibilities for the development of this disease:

Homozygous thalassemia (thalassemia major, severe illness)
Both copies of the β-globin genes contain nonsense mutations, so that the corresponding mRNAs are degraded by NMD and, as a result, no β-globin chains are formed.
Heterozygous thalassemia (thalassemia minor, mild disease)
Nonsense mutations are only found in one copy of the β-globin gene. NMD breaks down the mRNAs of the faulty gene so that only the healthy gene is expressed.
Heterozygous thalassemia (thalassemia intermedia, moderate disease)
The nonsense mutation is in the last exon of the mRNA (or in the last 50 base pairs of the penultimate). So there is no activation of the NMD (reason: see above) and both the healthy β-globin and the shortened β-globin are formed. The consequence of this is that the erythrocytes into which the defective β-globin is incorporated perish and the disease is therefore moderately severe.

Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is an X-linked recessive degenerative muscle disease. Accordingly, it is almost exclusively men who become ill, as the supplementary Y chromosome does not have a dominant function. A mutation in the dystrophin gene causes a frameshift with a nonsense mutation in the corresponding mRNA as a result. The NMD breaks down the mRNA, which results in a total loss of the dystrophin protein. This means that there are no shortened but possibly still functional or partially functional proteins.

The NMD also plays an important role in cancer , in which there is often an accumulation of mutations in the diseased cells.

literature

  • BP Lewis, RE Green, SE Brenner: Evidence for the widespread coupling of alternative splicing and nonsense-mediated mRNA decay in humans. In: Proc. Natl. Acad. Sci. USA 100 (1), 2003, pp. 189-192. PMID 12502788 (PDF)
  • EN Noensie, HC Dietz: A strategy for disease gene identification through nonsense-mediated mRNA decay inhibition. In: Nat. Biotechnol. 19 (5), 2001, pp. 434-439. PMID 11329012 . doi: 10.1038 / 88099
  • Y. Ishigaki, X. Li, G. Serin, LE Maquat : Evidence for a pioneer round of mRNA translation: mRNAs subject to nonsense-mediated decay in mammalian cells are bound by CBP80 and CBP20 . In: Cell . tape 106 , no. 5 , September 2001, p. 607-617 , PMID 11551508 .
  • N. Oh, KM Kim, H. Cho, J. Choe, YK Kim: Pioneer round of translation occurs during serum starvation . In: Biochem. Biophys. Res. Commun. tape 362 , no. 1 , October 2007, p. 145-151 , doi : 10.1016 / j.bbrc.2007.07.169 , PMID 17693387 .

Individual evidence

  1. ↑ Yao-Fu Chang, J. Saadi Imam, Miles F. Wilkinson: The Nonsense-Mediated Decay RNA Surveillance Pathway . In: Annual Review of Biochemistry . 2007, p. 51-74 .
  2. ↑ PA Fresh Meyer, HC Dietz: Nonsense-mediated mRNA decay in health and disease. In: Hum. Mol. Genet. Volume 8, No. 10, 1999, pp. 1893-1900. PMID 10469842 . (PDF)
  3. ↑ PH Byers: Killing the messenger: new insights into nonsense-mediated mRNA decay. In: J. Clin. Invest. Volume 109, No. 1, 2002, pp. 3-6. PMID 11781342 . (PDF)
  4. ↑ C. Schweingruber, SC Rufener, D. Zünd, A. Yamashita, O. Mühlemann: Nonsense-mediated mRNA decay - mechanisms of substrate mRNA recognition and degradation in mammalian cells. In: Biochim Biophys Acta. Volume 1829, No. 6-7, 2013, pp. 612-623. doi: 10.1016 / j.bbagrm.2013.02.005 . PMID 23435113 .
  5. ↑ I. Behm-Ansmant: Quality control of gene expression: a stepwise assembly pathway for the surveillance complex did triggers nonsense-mediated mRNA decay . In: Genes & Development . 20, No. 4, 2006, ISSN  0890-9369 , pp. 391-398. doi : 10.1101 / gad.1407606 .
  6. ^ LE Maquat : Nonsense-mediated mRNA decay in mammals. In: J. Cell. Sci. 118 (Pt 9), 2005, pp. 1773-1776. PMID 15860725 .
  7. ↑ J. Hwang, YK Kim: When a ribosome encounters a premature termination codon. In: BMB Rep. Volume 46, No. 1, 2013, pp. 9-16. PMID 23351378 . (PDF) ( Memento of the original from March 7, 2016 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. @1@ 2Template: Webachiv / IABot / www.bmbreports.org