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Double stranded RNA formation leads to preferential nuclear export and gene expression

ABSTRACT: mRNAs are transcribed and processed in the nucleus before they are exported into the cytoplasm for translation. Export is mediated by the export receptor heterodimer Mex67-Mtr2 in yeast (TAP-p15 in humans). Interestingly, also many lncRNAs leave the nucleus but it is currently unclear why they travel into the cytoplasm. Here we show that antisense (as)RNAs accelerate mRNA export by annealing with their sense counterparts through the helicase Dbp2. These double-stranded (ds)RNAs dominate export compared to single-stranded (ss)RNA, as they have a higher capacity and affinity for the export receptor Mex67. In this way, asRNAs boost gene expression, which is beneficial for cells. This is particularly important upon expression program changes. Consequently, the degradation or prevention of the formation of dsRNA is toxic for cells. This mechanism illuminates the general cellular occurrence of asRNAs and explains their nuclear export.

ORGANISM(S): Saccharomyces cerevisiae

PROVIDER: GSE252951 | GEO | 2024/04/30

REPOSITORIES: GEO

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Double-stranded RNA formation leads to preferential nuclear export and gene expression

Project description:mRNAs are transcribed and processed in the nucleus before they are exported into the cytoplasm for translation. Export is mediated by the export receptor heterodimer Mex67-Mtr2 in yeast (TAP-p10 in humans). Interestingly, also long non-coding RNAs (lncRNAs) leave the nucleus and so-called XUTs (Xrn1 sensitive unstable transcripts) accumulate in the cytoplasm of the degradation defective xrn1∆ mutant. Curiously, it is currently unclear why so many lncRNAs travel into the cytoplasm. Here we show that such ncRNAs accelerate mRNA export by annealing with their sense counterparts through the helicase Dbp2. These double stranded (ds) RNAs dominate export, because Mex67 has a higher affinity to dsRNAs and more molecules bind. Cells benefit from this mechanism as it quickly regulates gene expression, which is particularly important upon expression program changes. Consequently, prevention of the dsRNA formation or destroying dsRNAs is lethal to cells. This mechanism could explain the general cellular occurrence of antisense RNAs.

2024-04-30 | GSE188455 | GEO

Control of gene expression by Ott1/RBM15 protein

Project description:The conserved mRNA nuclear export receptor NXF1 (Mex67 in yeast) assembles with messenger ribonucleoproteins (mRNP) in the nucleus and guides them through the nuclear pore complex (NPC) into the cytoplasm. The DEAD-box RNA helicase Dbp5 is essential for nuclear export of mRNA and is thought to dissociate Mex67 from mRNP upon translocation, thereby generating directional passage. However, the molecular mechanism by which Dbp5 recognizes Mex67-containing mRNP is not clear. Here we report that the human NXF1-binding protein RBM15 binds to DBP5 specifically and enables its direct contact with mRNA. We found that RBM15 is enriched at the nuclear envelope and colocalizes with DBP5 at the NPC. Knockout of RBM15’s orthologue in mouse (Ott1) leads to global changes in mRNA expression and excessive mRNA accumulation in the cytoplasm, indicating an essential role of RBM15 in mRNA export regulation. We propose that RBM15 acts locally at the NPC, by transiently bridging the NXF1-mRNP complexes to DBP5, thereby contributing to the substrate specificity of mRNA export.

2008-06-18 | GSE11785 | GEO

Mip6 binds directly to the Mex67 UBA domain to maintain low levels of Msn2/4 stress dependent mRNAs

Project description:RNA binding proteins (RBPs) participate in almost all steps of gene expression, underscoring their potential as key regulators of RNA homeostasis. We structurally and functionally characterized Mip6, a four-RNA Recognition Motif (RRM)-containing RBP, as a functional and physical interactor of the mRNA export factor Mex67. Mip6 directly interacts with the ubiquitin-associated (UBA) domain of Mex67 through tryptophan 442 of Mip6-RRM4, whose mutation leads to slow growth of yeast cells in vivo. Although Mip6-RRM4 binds to RNA in vitro, Mex67 UBA binding prevents Mip6-RRM4 interaction with RNA. Mip6 shuttles between the nucleus and the cytoplasm in a Mex67-dependent manner and concentrates in cytoplasmic foci under several stressors. Photoactivatable Ribonucleoside-Enhanced Crosslinking and Immunoprecipitation (PAR-CLIP) experiments showed preferential binding of Mip6 to mRNAs regulated by the stress-response Msn2/4 transcription factors. Consistent with this binding, MIP6 deletion affected their export and expression levels. These results reveal a novel role for Mip6 in the homeostasis of Msn2/4 dependent transcripts by its direct interaction with Mex67 UBA domain.

2019-08-29 | GSE126236 | GEO

Quality control of spliced mRNAs requires the shuttling SR-proteins Gbp2 and Hrb1

Project description:Eukaryotic cells have to prevent the export of unspliced pre-mRNAs until intron removal is completed to avoid the expression of aberrant and potentially harmful proteins. Only mature RNAs associate with the export receptor Mex67 (mammalian TAP) and enter the cytoplasm. The underlying nuclear quality control mechanisms are still unclear. Here we show that two shuttling SR-proteins Gbp2 and Hrb1 are key surveillance factors for the selective export of spliced mRNAs in yeast. Their absence leads to the significant leakage of unspliced pre-mRNAs into the cytoplasm. They bind to pre-mRNAs and the spliceosome during splicing, where they are necessary for the surveillance of splicing and the stable binding of the TRAMP-complex to the spliceosome-bound transcripts. Faulty transcripts are marked for their degradation at the nuclear exosome. On correct mRNAs the SR-proteins recruit Mex67 upon completion of splicing to allow a quality controlled nuclear export. Altogether, these data identify a role for shuttling SR-proteins in mRNA surveillance and nuclear mRNA quality control. 6 samples, i.e. 2 replicates per protein Gbp2, Hrb1 and Npl3

2013-12-04 | E-GEOD-52808 | biostudies-arrayexpress

Quality control of spliced mRNAs requires the shuttling SR-proteins Gbp2 and Hrb1

2013-12-04 | GSE52808 | GEO

Light-Assisted Single-Stranded DNA Open-Chromatin Analysis in Single Spatially Localized Neuronal Cells Identifies the Capacity of Endogenous DNA to Act Catalytically [CHEX-seq]

Project description:We report a novel chromatin structure analysis technique, named "CHEX-seq" (CHromatin EXposed), which couples oligonucleotide random annealing and nucleus-resolution photoactivation such that the single-stranded open-chromatin DNA is copied, reverse transcribed, amplified and sequenced.

2023-10-19 | GSE231719 | GEO

Proximity labelling and cryomill affinity purification compared for Trypanosoma brucei proteins with unconfined, semi-confined and confined localisation

Project description:Identification of protein-protein interactions is a major contributor for understanding protein function and elucidating molecular and cellular mechanisms. Two strategies are currently popular for identification of protein interaction partners directly from the cellular environment. Affinity purification (pulldown) isolates the protein of interest with the aid of a matrix that specifically captures the target and potential partners. In BioID, the protein of interest is fused to biotin ligase facilitating proximity biotinylation and biotinylated proteins are isolated under stringent conditions with streptavidin. Whilst clear that these two methods can provide insight, it is also apparent that they can reveal distinct interactomes, but the basis for these differences is less obvious. We compare these methods using four different trypanosome proteins as baits: the cytoplasmic poly(A) binding proteins PABP1 and PABP2, mRNA export receptor MEX67, that shuttles between the nucleus and the cytoplasm with predominant localisation at the nuclear pores, and the nucleoporin NUP158.

2022-11-30 | PXD031245 | Pride

Xrn1-sensitive lncRNAs are insensitive to Dbp2 nuclear depletion

Project description:To investigate whether the action of Dbp2 on Xrn1-sensitive lncRNAs depends on a nuclear or cytoplasmic localization, we used the anchor-away approach to deplete a Dbp2-FRB-GFP fusion from the nucleus upon rapamycin treatment.

2023-07-27 | GSE235551 | GEO

Transcription profiling of human total or cytoplamsic RNA from peripheral blood mononuclear cells expressing HTLV-I p30 to asses the ability of p30 to regulate the export of cellular transcripts to the cytoplasm

Project description:The Human T-cell Leukemia Virus (HTLV)-type-I non-structural protein p30 plays an important role in virus transmission and gene regulation. p30 has been documented to inhibit the export of certain viral mRNA transcripts from the nucleus to the cytoplasm. This nuclear retainment of RNA molecules essentially results in gene silencing, where protein products are not produced. Considering this unique function of p30, we used microarray analysis to assess the ability of p30 to inhibit not only the regulation of transcription of cellular genes, but also the ability of p30 to regulate the export of cellular transcripts to the cytoplasm. Experiment Overall Design: Total or cytoplamsic RNA from peripheral blood mononuclear cells expressing HTLV-I p30 was isolated and analyzed by microarray analysis, in comparison with mock-transcuced cells.

2009-10-16 | E-GEOD-16098 | biostudies-arrayexpress

Proteins that interact physically with Drosophila blanks

Project description:RNA interference targets aberrant transcripts with cognate small interfering RNAs, which derive from double-stranded RNA precursors through nucleolytic processing. Several functional screens have identified Drosophila blanks/lump (CG10630) as a facilitator of RNAi in cultured cells, yet its molecular function has remained unknown. The protein carries two dsRNA binding domains (dsRBD) and blanks mutant males have a spermatogenesis defect. We demonstrate that blanks selectively boosts RNAi triggered by dsRNA of nuclear origin. Blanks binds dsRNA in vitro, shuttles between nucleus and cytoplasm and the abundance of certain endogenous siRNAs is reduced in blanks mutant testes. Transgenic expression of a Blanks protein variant with increased nuclear retention reduces endogenous siRNA abundance unless the protein also carries a mutation that prevents binding of dsRNA to the second dsRBD. Blanks thus facilitates the export of dsRNA to the cytoplasm for further processing by the canonical RNAi machinery. In contrast, rescue of male fertility in blanks mutant animals was independent of RNA binding to the second dsRBD, consistent with a previous report that linked fertility to the first dsRBD of Blanks. The role of blanks in spermatogenesis appears thus unrelated to its role in dsRNA export.

2020-05-26 | PXD013792 | Pride

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