The Exon Junction Complex Core Represses Cancer-Specific Mature mRNA Re-splicing: A Potential Key Role in Terminating Splicing

Otani, Yuta; Fujita, Ken‐ichi; Kameyama, Tetsuya; Mayeda, Akila

doi:10.3390/ijms22126519

Cited by 13 publications

(8 citation statements)

References 25 publications

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“…Knockdown or depletion of EJC members lead to alterations in splicing profiles, including the occurrence of recursive splicing and generation of aberrant splicing isoforms. These effects were observed both in humans and Drosophila cells, indicating that the EJC has a conserved function in “safe-guarding” the splicing process (Blazquez et al, 2018; Joseph and Lai, 2021; Otani et al, 2021). Genomic studies have shown differences in EJC loading across junctions within a given transcript (Saulière et al, 2010; Singh et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

The paralogues MAGOH and MAGOHB are oncogenic factors in high-grade gliomas and safeguard the splicing of cell division and cell cycle genes

Barreiro

Guardia

Meliso

et al. 2022

Preprint

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The exon junction complex (EJC) plays key roles throughout the lifespan of RNA and is particularly relevant in the nervous system. We investigated the roles of two EJC members, the paralogs MAGOH and MAGOHB, with respect to brain tumor development. High MAGOH/MAGOHB expression was observed in 14 tumor types; glioblastoma (GBM) showed the greatest difference compared to normal tissue. Increased MAGOH/MAGOHB expression was associated with poor prognosis in glioma patients, while knockdown of MAGOH/MAGOHB affected different cancer phenotypes. Reduced MAGOH/MAGOHB expression in GBM cells caused alterations in the splicing profile, including re-splicing and skipping of multiple exons. The binding profiles of EJC proteins indicated that exons affected by MAGOH/MAGOHB knockdown accumulated fewer complexes on average, providing a possible explanation for their sensitivity to MAGOH/MAGOHB knockdown. Transcripts (genes) showing alterations in the splicing profile are mainly implicated in cell division, cell cycle, splicing, and translation. We propose that high MAGOH/MAGOHB levels are required to safeguard the splicing of genes in high demand in scenarios requiring increased cell proliferation (brain development and GBM growth), ensuring efficient cell division, cell cycle regulation, and gene expression (splicing and translation). Since differentiated neuronal cells do not require increased MAGOH/MAGOHB expression, targeting these paralogs is a potential option for treating GBM.

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Section: Discussionmentioning

confidence: 99%

The paralogues MAGOH and MAGOHB are oncogenic factors in high-grade gliomas and safeguard the splicing of cell division and cell cycle genes

Barreiro

Guardia

Meliso

et al. 2022

Preprint

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“…EJCs loaded onto spliced mRNAs play multiple roles in post-transcriptional gene regulation, including splicing, mRNA export, translation, and NMD [28][29][30]. In addition, recent investigations have revealed that EJCs increase mRNA fidelity by preventing over-splicing or re-splicing events of mature mRNAs [31,32]. As most translation termination codons are located in the last exon, EJCs are efficiently removed by translating ribosomes.…”

Section: Molecular Mechanism Underlying Nmdmentioning

confidence: 99%

UPF1: From mRNA Surveillance to Protein Quality Control

2021

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Selective recognition and removal of faulty transcripts and misfolded polypeptides are crucial for cell viability. In eukaryotic cells, nonsense-mediated mRNA decay (NMD) constitutes an mRNA surveillance pathway for sensing and degrading aberrant transcripts harboring premature termination codons (PTCs). NMD functions also as a post-transcriptional gene regulatory mechanism by downregulating naturally occurring mRNAs. As NMD is activated only after a ribosome reaches a PTC, PTC-containing mRNAs inevitably produce truncated and potentially misfolded polypeptides as byproducts. To cope with the emergence of misfolded polypeptides, eukaryotic cells have evolved sophisticated mechanisms such as chaperone-mediated protein refolding, rapid degradation of misfolded polypeptides through the ubiquitin–proteasome system, and sequestration of misfolded polypeptides to the aggresome for autophagy-mediated degradation. In this review, we discuss how UPF1, a key NMD factor, contributes to the selective removal of faulty transcripts via NMD at the molecular level. We then highlight recent advances on UPF1-mediated communication between mRNA surveillance and protein quality control.

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“…Recent transcriptome-wide analysis indicated that the ASAP and PSAP complexes regulate distinct alternative splicing either in EJC core-dependent or -independent manner (14). On the other hand, the EJC core alone, without any peripheral factors, plays a role in terminating splicing; i.e., repression of aberrant re-splicing on mature mRNA in cancer cells (15). Many lines of evidence support ASAP and PSAP complexes, with or without EJC core, as regulators of alternative splicing (reviewed in 7).…”

Section: Introductionmentioning

confidence: 99%

RNPS1 in PSAP complex controls periodic pre-mRNA splicing over the cell cycle

Fukumura,

Masuda,

Takeda

et al. 2023

Preprint

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Cell cycle progression must require periodic gene expression through the control of splicing. However, the splicing factors that directly control this cell cycle-dependent splicing remain unknown. Cell cycle-dependent expression of theAURKB(aurora kinase B) gene is essential for chromosome segregation and cytokinesis and we previously reported that RNPS1 is essential to maintain precise splicing inAURKBintron 5. Here we show that RNPS1 plays this role in PSAP complex with PNN (PININ) and SAP18, but not in ASAP complex with ACIN1 (ACINUS) and SAP18. A transcriptome-wide analysis of RNPS1- and PNN-deficient cells indicated that the PSAP complex globally controls pre-mRNA splicing during cell cycle progression. Remarkably, protein expression of RNPS1, but not PNN, is cell cycle-dependently coordinated with splicing in PSAP-controlled introns, includingAURKBintron 5, implicating RNPS1 as a key factor controlling periodic splicing during the cell cycle.GRAPHICAL ABSTRACT

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The Exon Junction Complex Core Represses Cancer-Specific Mature mRNA Re-splicing: A Potential Key Role in Terminating Splicing

Cited by 13 publications

References 25 publications

The paralogues MAGOH and MAGOHB are oncogenic factors in high-grade gliomas and safeguard the splicing of cell division and cell cycle genes

The paralogues MAGOH and MAGOHB are oncogenic factors in high-grade gliomas and safeguard the splicing of cell division and cell cycle genes

UPF1: From mRNA Surveillance to Protein Quality Control

RNPS1 in PSAP complex controls periodic pre-mRNA splicing over the cell cycle

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