A nuclear role for the DEAD-box protein Dbp5 in tRNA export

Lari, Abdolaziz Rastegar; Rajan, Arvind Arul Nambi; Sandhu, Rima; Reiter, Taylor; Montpetit, Rachel; Young, Barry P.; Loewen, Chris; Montpetit, Ben

doi:10.7554/elife.48410

Cited by 17 publications

(35 citation statements)

References 79 publications

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“…Our data and our resulting model are consistent with a recent report that defined the nuclear export signal (NES) for Dbp5 and concluded that nuclear shuttling is not essential for mRNA export [33]. The discovery of an NES in Dbp5 establishes that nuclear export of Dbp5 itself is not dependent on mRNA export, in agreement with the lack of nuclear Dbp5 enrichment observed in rat7-1 and gle1-4 mutants (Fig 1).…”

Section: Discussionsupporting

confidence: 92%

“…Given the recently described nuclear role for the human Dbp5 homologue DDX19B [32] and the suggested function for Dbp5 during tRNA processing in the nucleus [33], a more detailed knowledge of Dbp5's mode and site(s) of interaction with the mRNP is critical to understanding Dbp5 functions. In this study, we present several lines of evidence that Dbp5 association with the mRNP prior to export is not required for its remodeling activity at the NPC.…”

Section: Discussionmentioning

confidence: 99%

“…These enzymes perform their functions through three primary modes of action: as RNA helicases to unwind short RNA-RNA or RNA-DNA duplexes, as RNP remodelers to disrupt specific protein-RNA interactions, or as stable RNA binding proteins that scaffold other interactions [reviewed in 27]. In addition to its essential function in mRNA export, Dbp5 regulates translation termination in the cytoplasm, and, notably, nuclear roles for Dbp5 and its human Dbp5 homologue DDX19B were recently described [28][29][30][31][32][33]. Structurally, DEAD-box proteins (Dbps in yeast, DDXs in humans) contain two globular RecA domains that are joined by a flexible linker [12,34,35].…”

Section: Introductionmentioning

confidence: 99%

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Dbp5 associates with RNA-bound Mex67 and Nab2 and its localization at the nuclear pore complex is sufficient for mRNP export and cell viability

Adams

Wente

2020

PLoS Genet

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In Saccharomyces cerevisiae, the mRNA export receptor Mex67 is recruited to mature nuclear transcripts to mediate mRNA export through the nuclear pore complex (NPC) to the cytoplasm. Mex67 binds transcripts through adaptor proteins such as the poly(A) binding protein Nab2. When a transcript reaches the cytoplasmic face of the NPC, the DEADbox protein Dbp5 acts to induce a local structural change to release Nab2 and Mex67 in an essential process termed mRNP remodeling. It is unknown how certain proteins (Nab2, Mex67) are released during Dbp5-mediated mRNP remodeling, whereas others remain associated. Here, we demonstrate that Dbp5 associates in close proximity with Mex67 and Nab2 in a cellular complex. Further, fusion of Dbp5 to Nup159 anchors Dbp5 at the cytoplasmic face of the NPC and is sufficient for cell viability. Thus, we speculate that the essential role of Dbp5 in remodeling exporting mRNPs requires its localization to the NPC and is separable from other subcellular functions of Dbp5. This work supports a model where the diverse nuclear, cytoplasmic and NPC functions of Dbp5 in the mRNA lifecycle are not interdependent and that Dbp5 is locally recruited through complex protein-protein interactions to select regions of transcripts for specific removal of transport proteins at the NPC.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dbp5 associates with RNA-bound Mex67 and Nab2 and its localization at the nuclear pore complex is sufficient for mRNP export and cell viability

Adams

Wente

2020

PLoS Genet

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“…Single molecule and polyA-RNA FISH was performed as described in ( 81 , 82 ), with the exception that smiFISH probes were used to detect gene transcripts by single molecule FISH ( 83 ). At indicated time points, ∼3.5 OD of meiotic cultures was fixed with 37% formaldehyde for 20 min at room temperature followed by overnight at 4°C.…”

Section: Methodsmentioning

confidence: 99%

The SR-protein Npl3 is an essential component of the meiotic splicing regulatory network in Saccharomyces cerevisiae

Sandhu

Sinha

Montpetit

2021

Nucleic Acids Research

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The meiotic gene expression program in Saccharomyces cerevisiae involves regulated splicing of meiosis-specific genes via multiple splicing activators (e.g. Mer1, Nam8, Tgs1). Here, we show that the SR protein Npl3 is required for meiotic splicing regulation and is essential for proper execution of the meiotic cell cycle. The loss of Npl3, though not required for viability in mitosis, caused intron retention in meiosis-specific transcripts, inefficient meiotic double strand break processing and an arrest of the meiotic cell cycle. The targets of Npl3 overlapped in some cases with other splicing regulators, while also having unique target transcripts that were not shared. In the absence of Npl3, splicing defects for three transcripts (MER2, HOP2 and SAE3) were rescued by conversion of non-consensus splice sites to the consensus sequence. Methylation of Npl3 was further found to be required for splicing Mer1-dependent transcripts, indicating transcript-specific mechanisms by which Npl3 supports splicing. Together these data identify an essential function for the budding yeast SR protein Npl3 in meiosis as part of the meiotic splicing regulatory network.

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“…Dbp5 is localized in the nucleus, in the cytoplasm and concentrated around the nuclear rim [27,32]. A nuclear export signal and a nuclear import signal were identified in the N-terminus of the protein, enabling shuttling between the compartments [33]. The helicase core of Dbp5 is composed of two highly conserved RecA-like domains linked by a hinge region [34].…”

Section: The Function Of Dbp5 In Translation Terminationmentioning

confidence: 99%

Dbp5/DDX19 between Translational Readthrough and Nonsense Mediated Decay

Beißel

Große

Krebber

2020

IJMS

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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.

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A nuclear role for the DEAD-box protein Dbp5 in tRNA export

Cited by 17 publications

References 79 publications

Dbp5 associates with RNA-bound Mex67 and Nab2 and its localization at the nuclear pore complex is sufficient for mRNP export and cell viability

Dbp5 associates with RNA-bound Mex67 and Nab2 and its localization at the nuclear pore complex is sufficient for mRNP export and cell viability

The SR-protein Npl3 is an essential component of the meiotic splicing regulatory network in Saccharomyces cerevisiae

Dbp5/DDX19 between Translational Readthrough and Nonsense Mediated Decay

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