Dbp5/DDX19 between Translational Readthrough and Nonsense Mediated Decay

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.

FOXC2 Disease Mutations Identified in Lymphedema Distichiasis Patients Impair Transcriptional Activity and Cell Proliferation

“…The majority of FOXC2 mutations linked to lymphedema-distichiasis syndrome are insertion/deletion (73%) and nonsense mutations (10%) ( Figure 1 B) [ 2 , 21 , 22 , 23 ]. In most cases, they are presumed to cause loss of the gene product because their mRNAs contain a premature termination codon (PTC) and are thus eliminated through the nonsense-mediated decay (NMD) pathway [ 24 ]. However, in the specific case of FOXC2, NMD should only be considered a theoretical hypothesis, because no data is available on the lack of FOXC2 mutated mRNAs or proteins in different biological tissues of affected subjects.…”

A potential function for the helicase Dbp5 in cytoplasmic quality control

“…Since termination at a PTC also requires eRF1 and eRF3, it seems likely that the function of Dbp5 may also influence NMD, which has already been suggested (29). However, experimental support for this is currently missing.…”

“…The in vivo co-IP studies were carried out according to the protocols published previously (29)(30)(31) For immunoprecipitation of GFP-and MYC-tagged proteins, 10 µl slurry of GFP-or MYC-Trap ® _A beads (Chromotek) were used per reaction and incubated with 1000 µl of the cleared yeast lysate for 3 h under rotating at 8°C. Subsequently, the immunoprecipitated proteins were washed 3-5 times with PBSKMT buffer.…”

Melatonin: Regulation of Biomolecular Condensates in Neurodegenerative Disorders

“…Therefore, a low level of RNA with negative charge could interact with positively charged proteins to promote phase separation and the formation of transcriptional condensates, whereas high levels of negatively charged RNA could repel proteins with positive charges to dissolve condensates [ 525 ]. In the regulation of MLO assembly and disassembly dynamics, DDXs such as DDX3, DDX4, and DDX6 may function as molecular switches that direct mRNA into RNA granules such as P-bodies and stress granules for transient storage or decay, as well as the timely, necessary resolution and disassembly of these granules [ 49 , 1073 , 1074 , 1075 , 1076 , 1077 ]. It is important to note that the export of nuclear mRNA into cytoplasm is regulated by DDX19, an ATP-dependent RNA helicase with many important functions [ 1078 ].…”

“…Since its discovery in Saccharomyces cerevisiae in 1999, DX19 (human)/Dbp5 (yeast) [ 1079 ] has been associated with important functions involving mRNA export and remodeling [ 1062 , 1079 , 1080 , 1081 ], mRNA expression [ 1082 ], and translation [ 1076 ], as well as DNA transcription and metabolism [ 1083 , 1084 ]. One of the most important functions of DDX19 in the context of MLO dynamics is the export of nuclear mRNA via nuclear pore complexes (NPCs).…”