RBM33 directs the nuclear export of transcripts containing GC-rich elements

Thomas, Anu; Rehfeld, Frederick; Zhang, He; Chang, Tong; Goodarzi, Mohammad; Gillet, Frank; Mendell, Joshua T.

doi:10.1101/gad.349456.122

Cited by 16 publications

(10 citation statements)

References 62 publications

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“…Additionally, it is known that mRNAs with high GC content at the 5’ end of cellular mRNAs are more efficiently exported from the nucleus than mRNAs with low GC content 13 , which may need additional factors, such as GANP, to facilitate export. Recently, the RBM33 protein was shown to bind to high GC stretches on mRNAs and recruit NXF1 for their export 20 . We found that the GANP-dependent mRNAs have a lower overall GC content than the GANP-independent mRNAs including regions within the first 75 nt at the 5’ end, therefore it is possible that GANP-independent mRNAs may use small GC-rich regions to recruit mRNA export factors to mediate export independent or less dependent on GANP.…”

Section: Discussionmentioning

confidence: 99%

Influenza virus mRNAs encode determinants for nuclear export via the cellular TREX-2 complex

et al. 2023

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Nuclear export of influenza A virus (IAV) mRNAs occurs through the nuclear pore complex (NPC). Using the Auxin-Induced Degron (AID) system to rapidly degrade proteins, we show that among the nucleoporins localized at the nucleoplasmic side of the NPC, TPR is the key nucleoporin required for nuclear export of influenza virus mRNAs. TPR recruits the TRanscription and EXport complex (TREX)−2 to the NPC for exporting a subset of cellular mRNAs. By degrading components of the TREX-2 complex (GANP, Germinal-center Associated Nuclear Protein; PCID2, PCI domain containing 2), we show that influenza mRNAs require the TREX-2 complex for nuclear export and replication. Furthermore, we found that cellular mRNAs whose export is dependent on GANP have a small number of exons, a high mean exon length, long 3’ UTR, and low GC content. Some of these features are shared by influenza virus mRNAs. Additionally, we identified a 45 nucleotide RNA signal from influenza virus HA mRNA that is sufficient to mediate GANP-dependent mRNA export. Thus, we report a role for the TREX-2 complex in nuclear export of influenza mRNAs and identified RNA determinants associated with the TREX-2-dependent mRNA export.

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Section: Discussionmentioning

confidence: 99%

Influenza virus mRNAs encode determinants for nuclear export via the cellular TREX-2 complex

et al. 2023

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“…In our hands, the relevance of GCcds is clearly picked up by both the Random Forest and the Lasso (Supplementary Figure 4). Importantly, we included similar features, such as overall GC content 24 , in UTRs, introns etc., alongside codon frequencies 20 and previously estimated values of codon optimality.…”

Section: Discussionmentioning

confidence: 99%

A ubiquitous GC content signature underlies multimodal mRNA regulation by DDX3X

Jowhar

Venkataramanan³

et al. 2023

Preprint

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The road from transcription to protein synthesis is paved with many obstacles, allowing for several modes of post-transcriptional regulation of gene expression. A fundamental player in mRNA biology is DDX3X, an RNA binding protein that canonically regulates mRNA translation. By monitoring dynamics of mRNA abundance and translation following DDX3X depletion, we observe stabilization of translationally suppressed mRNAs. We use interpretable statistical learning models to uncover GC content in the coding sequence as the major feature underlying RNA stabilization. This result corroborates GC content-related mRNA regulation detectable in other studies, including hundreds of ENCODE datasets and recent work focusing on mRNA dynamics in the cell cycle. We provide further evidence for mRNA stabilization by detailed analysis of RNA-seq profiles in hundreds of samples, including a Ddx3x conditional knockout mouse model exhibiting cell cycle and neurogenesis defects. Our study identifies a ubiquitous feature underlying mRNA regulation and highlights the importance of quantifying multiple steps of the gene expression cascade, where RNA abundance and protein production are often uncoupled.

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“…Co-immunoprecipitation (CoIP) was performed as previously described ( 58 ), with modifications. Three days after infection, cells were scraped in ice-cold PBS and lysed in 800 μl of lysis buffer [50 mM tris-HCl at pH 7.5, 150 mM NaCl, 1% NP-40, 0.1% sodium deoxycholate, and 2× protease inhibitor tablet (Roche)] for 30 min on ice and cleared by centrifugation at 14,000 g for 10 min at 4°C.…”

Section: Methodsmentioning

confidence: 99%

TWIST2-mediated chromatin remodeling promotes fusion-negative rhabdomyosarcoma

et al. 2023

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Rhabdomyosarcoma (RMS) is a common soft tissue sarcoma in children that resembles developing skeletal muscle. Unlike normal muscle cells, RMS cells fail to differentiate despite expression of the myogenic determination protein MYOD. The TWIST2 transcription factor is frequently overexpressed in fusion-negative RMS (FN-RMS). TWIST2 blocks differentiation by inhibiting MYOD activity in myoblasts, but its role in FN-RMS pathogenesis is incompletely understood. Here, we show that knockdown of TWIST2 enables FN-RMS cells to exit the cell cycle and undergo terminal myogenesis. TWIST2 knockdown also substantially reduces tumor growth in a mouse xenograft model of FN-RMS. Mechanistically, TWIST2 controls H3K27 acetylation at distal enhancers by interacting with the chromatin remodelers SMARCA4 and CHD3 to activate growth-related target genes and repress myogenesis-related target genes. These findings provide insights into the role of TWIST2 in maintaining an undifferentiated and tumorigenic state of FN-RMS and highlight the potential of suppressing TWIST2-regulated pathways to treat FN-RMS.

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RBM33 directs the nuclear export of transcripts containing GC-rich elements

Cited by 16 publications

References 62 publications

Influenza virus mRNAs encode determinants for nuclear export via the cellular TREX-2 complex

Influenza virus mRNAs encode determinants for nuclear export via the cellular TREX-2 complex

A ubiquitous GC content signature underlies multimodal mRNA regulation by DDX3X

TWIST2-mediated chromatin remodeling promotes fusion-negative rhabdomyosarcoma

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