Abstract
The DEAD-box protein Dbp5 (human DDX19) remodels RNA-protein complexes. Dbp5 functions in ribonucleoprotein export and translation termination. Termination occurs, when the ribosome has reached a stop codon through the Dbp5 mediated delivery of the eukaryotic termination factor eRF1. eRF1 contacts eRF3 upon dissociation of Dbp5, resulting in polypeptide chain release and subsequent ribosomal subunit splitting. Mutations in DBP5 lead to stop codon readthrough, because the eRF1 and eRF3 interaction is not controlled and occurs prematurely. This identifies Dbp5/DDX19 as a possible potent drug target for nonsense suppression therapy. Neurodegenerative diseases and cancer are caused in many cases by the loss of a gene product, because its mRNA contained a premature termination codon (PTC) and is thus eliminated through the nonsense mediated decay (NMD) pathway, which is described in the second half of this review. We discuss translation termination and NMD in the light of Dbp5/DDX19 and subsequently speculate on reducing Dbp5/DDX19 activity to allow readthrough of the PTC and production of a full-length protein to detract the RNA from NMD as a possible treatment for diseases.
Highlights
The DEAD-box protein Dbp5 remodels RNA-protein complexes
The cytoplasmic quality control system ensures integrity of the mRNA open reading frame by monitoring ribosomal decoding. If this is not the case and the ribosome stalls without encountering a stop codon, those transcripts are eliminated by the no-go decay (NGD) and no-stop decay (NSD)
When a premature termination codon (PTC) is detected, mRNA degradation occurs via the nonsense mediated decay (NMD) [4,5]
Summary
On normal mRNAs, translation initiation is followed by elongation and ends with termination. Translation termination comprises three key events: (1) Recognition of the stop codon, (2) hydrolysis of the terminal peptidyl-tRNA bond and polypeptide chain release, and (3) ribosome recycling and disassembly of the termination complex. As soon as one of the three stop codons is reached on the RNA, the eukaryotic release factor eRF1 (encoded by SUP45 in yeast) binds to the ribosomal A-site. The C-terminal domain of eRF1 contacts eRF3, leading to its GTP-binding and subsequent hydrolysis and results in a conformational change important for proper termination [14,15]. The ribosomes are split, resulting in free 60S subunit and a 40S subunit bound to mRNA and the deacylated tRNA, and subsequently, the post-termination complexes are disassembled. Because it has an additional well-known function in mRNA export and because identification of its function abrogated the prior view that eRF1 and eRF3 would enter the ribosome together
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