scholarly journals Mammalian UPF3A and UPF3B activate NMD independently of their EJC binding

2021 ◽  
Author(s):  
Zhongxia Yi ◽  
René M Arvola ◽  
Sean Myers ◽  
Corinne N Dilsavor ◽  
Rabab Abu Alhasan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Active Role ◽  
Exon Junction Complex ◽  
Human Cell Lines ◽  
Wild Type ◽  
Human Colorectal Cancer ◽  
Independent Manner ◽  
Exon Junction ◽  
Nonsense Mediated Mrna Decay ◽  
Hct116 Cells

Nonsense-mediated mRNA decay (NMD) is governed by the three conserved factors - UPF1, UPF2 and UPF3. While all three are required for NMD in yeast, UPF3B is dispensable for NMD in mammals, with its paralog UPF3A suggested to only weakly activate or even repress NMD due to its weaker binding to the exon junction complex (EJC). Here we characterize the UPF3B-dependent and -independent NMD in human cell lines knocked-out of one or both UPF3 paralogs. We show that in human colorectal cancer HCT116 cells, EJC-mediated NMD can operate in UPF3B-dependent and -independent manner. While UPF3A is almost completely dispensable for NMD in wild-type cells, it strongly activates EJC-mediated NMD in cells lacking UPF3B. Surprisingly, this major NMD branch can operate in UPF3-independent manner questioning the idea that UPF3 is needed to bridge UPF proteins to the EJC during NMD. Complementation studies in UPF3 knockout cells further show that EJC-binding domain of UPF3 paralogs is not essential for NMD. Instead, the conserved mid domain of UPF3B, previously shown to engage with ribosome release factors, is required for its full NMD activity. Altogether, UPF3 plays a more active role in NMD than simply being a bridge between the EJC and the UPF complex.

scholarly journals A novel class of inhibitors that target SRSF10 and promote p53-mediated cytotoxicity on human colorectal cancer cells

NAR Cancer ◽  
2021 ◽  
Vol 3 (2) ◽  
Author(s):  
Muhammad Sohail ◽  
Lulzim Shkreta ◽  
Johanne Toutant ◽  
Safwat Rabea ◽  
Jean-Philippe Babeu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Small Molecules ◽  
Human Colorectal Cancer ◽  
Independent Manner ◽  
Colorectal Cancer Cells ◽  
Elevated Expression ◽  
Splicing Regulator ◽  
Tumorigenic Activity ◽  
Human Colorectal Cancer Cells ◽  
Hct116 Cells

Abstract The elevated expression of the splicing regulator SRSF10 in metastatic colorectal cancer (CRC) stimulates the production of the pro-tumorigenic BCLAF1-L splice variant. We discovered a group of small molecules with an aminothiazole carboxamide core (GPS167, GPS192 and others) that decrease production of BCLAF1-L. While additional alternative splicing events regulated by SRSF10 are affected by GPS167/192 in HCT116 cells (e.g. in MDM4, WTAP, SLK1 and CLK1), other events are shifted in a SRSF10-independent manner (e.g. in MDM2, NAB2 and TRA2A). GPS167/192 increased the interaction of SRSF10 with the CLK1 and CLK4 kinases, leading us to show that GPS167/192 can inhibit CLK kinases preferentially impacting the activity of SRSF10. Notably, GPS167 impairs the growth of CRC cell lines and organoids, inhibits anchorage-independent colony formation, cell migration, and promotes cytoxicity in a manner that requires SRSF10 and p53. In contrast, GPS167 only minimally affects normal colonocytes and normal colorectal organoids. Thus, GPS167 reprograms the tumorigenic activity of SRSF10 in CRC cells to elicit p53-dependent apoptosis.

scholarly journals Exon-Junction Complex Components Specify Distinct Routes of Nonsense-Mediated mRNA Decay with Differential Cofactor Requirements

2005 ◽  
Vol 20 (1) ◽  
pp. 65-75 ◽  
Author(s):  
Niels H. Gehring ◽  
Joachim B. Kunz ◽  
Gabriele Neu-Yilik ◽  
Stephen Breit ◽  
Marcelo H. Viegas ◽  
...  
Keyword(s):  
Mrna Decay ◽  
Exon Junction Complex ◽  
Exon Junction ◽  
Nonsense Mediated Mrna Decay ◽  
Complex Components

scholarly journals The prototype γ-2 herpesvirus nucleocytoplasmic shuttling protein, ORF 57, transports viral RNA through the cellular mRNA export pathway

2005 ◽  
Vol 387 (2) ◽  
pp. 295-308 ◽  
Author(s):  
Ben J. L. WILLIAMS ◽  
James R. BOYNE ◽  
Delyth J. GOODWIN ◽  
Louise ROADEN ◽  
Guillaume M. HAUTBERGUE ◽  
...  
Keyword(s):  
Nuclear Export ◽  
Mammalian Cells ◽  
Mrna Export ◽  
Dominant Negative ◽  
Viral Rna ◽  
Exon Junction Complex ◽  
Independent Manner ◽  
Exon Junction ◽  
Export Pathway ◽  
Rna Export

HVS (herpesvirus saimiri) is the prototype γ-2 herpesvirus. This is a subfamily of herpesviruses gaining importance since the identification of the first human γ-2 herpesvirus, Kaposi's sarcoma-associated herpesvirus. The HVS ORF 57 (open reading frame 57) protein is a multifunctional transregulatory protein homologous with genes identified in all classes of herpesviruses. Recent work has demonstrated that ORF 57 has the ability to bind viral RNA, shuttles between the nucleus and cytoplasm and promotes the nuclear export of viral transcripts. In the present study, we show that ORF 57 shuttles between the nucleus and cytoplasm in a CRM-1 (chromosomal region maintenance 1)-independent manner. ORF 57 interacts with the mRNA export factor REF (RNA export factor) and two other components of the exon junction complex, Y14 and Magoh. The association of ORF 57 with REF stimulates recruitment of the cellular mRNA export factor TAP (Tip-associated protein), and HVS infection triggers the relocalization of REF and TAP from the nuclear speckles to several large clumps within the cell. Using a dominant-negative form of TAP and RNA interference to deplete TAP, we show that it is essential for bulk mRNA export in mammalian cells and is required for ORF 57-mediated viral RNA export. Furthermore, we show that the disruption of TAP reduces viral replication. These results indicate that HVS utilizes ORF 57 to recruit components of the exon junction complex and subsequently TAP to promote viral RNA export through the cellular mRNA export pathway.

scholarly journals The Exon Junction Complex Undergoes a Compositional Switch that Alters mRNP Structure and Nonsense-Mediated mRNA Decay Activity

Cell Reports ◽  
2018 ◽  
Vol 25 (9) ◽  
pp. 2431-2446.e7 ◽  
Author(s):  
Justin W. Mabin ◽  
Lauren A. Woodward ◽  
Robert D. Patton ◽  
Zhongxia Yi ◽  
Mengxuan Jia ◽  
...  
Keyword(s):  
Mrna Decay ◽  
Exon Junction Complex ◽  
Exon Junction ◽  
Nonsense Mediated Mrna Decay

scholarly journals A Day in the Life of the Exon Junction Complex

Biomolecules ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 866 ◽  
Author(s):  
Lena P. Schlautmann ◽  
Niels H. Gehring
Keyword(s):  
Mrna Export ◽  
Mrna Splicing ◽  
Exon Junction Complex ◽  
Chronological Order ◽  
Exon Junction ◽  
Messenger Ribonucleoprotein ◽  
Associated Proteins ◽  
Core Components ◽  
Nonsense Mediated Mrna Decay ◽  
Exon Junctions

The exon junction complex (EJC) is an abundant messenger ribonucleoprotein (mRNP) component that is assembled during splicing and binds to mRNAs upstream of exon-exon junctions. EJCs accompany the mRNA during its entire life in the nucleus and the cytoplasm and communicate the information about the splicing process and the position of introns. Specifically, the EJC’s core components and its associated proteins regulate different steps of gene expression, including pre-mRNA splicing, mRNA export, translation, and nonsense-mediated mRNA decay (NMD). This review summarizes the most important functions and main protagonists in the life of the EJC. It also provides an overview of the latest findings on the assembly, composition and molecular activities of the EJC and presents them in the chronological order, in which they play a role in the EJC’s life cycle.

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