4EHP and GIGYF1/2 Mediate Translation-Coupled Messenger RNA Decay

Weber, Ramona; Chung, Min-Yi; Zinnall, Ulrike; Landthaler, Markus; Valkov, Eugene; Izaurralde, Elisa; Igreja, Cátia

doi:10.2139/ssrn.3548260

Cited by 12 publications

(23 citation statements)

References 35 publications

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“…It is, therefore, possible that the yeast Not3 ortholog CNOT3 anchors the CCR4‐NOT complex to the slow ribosome via the E site in vertebrates (Collart & Panasenko, 2017; Buschauer et al , 2020). Ubiquitination site(s) on the ribosome and downstream NGD effectors are also conserved in vertebrates (Garzia et al , 2017; Juszkiewicz & Hegde, 2017; Matsuo et al , 2017; Sundaramoorthy et al , 2017; Juszkiewicz et al , 2018, 2020; D’Orazio et al , 2019; Ikeuchi et al , 2019; Weber et al , 2020). Future studies will investigate the conservation and biological function of codon‐mediated decay and NGD.…”

Section: Discussionmentioning

confidence: 99%

“…RQC is conserved in mammals, in which the Hel2 ortholog Znf598 acts as a collision sensor (Garzia et al , 2017; Juszkiewicz & Hegde, 2017; Sundaramoorthy et al , 2017; Juszkiewicz et al , 2018). In contrast, the occurrence of NGD is controversial in vertebrates: the established RQC substrate, consecutive Lys AAA codons, does not promote apparent mRNA decay in vertebrates (Juszkiewicz & Hegde, 2017), whereas recruitment of the Znf598‐4EHP‐GIGYF1/2 complex on paused ribosomes promotes mRNA decay (Weber et al , 2020). Hence, it remains unclear whether the codon effects captured by genome‐wide analyses in vertebrates are entirely attributable to codon‐mediated decay since they may include the effect of NGD‐related pathways.…”

Section: Introductionmentioning

confidence: 99%

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Ribosome slowdown triggers codon‐mediated mRNA decay independently of ribosome quality control

et al. 2022

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The control of mRNA stability plays a central role in regulating gene expression patterns. Recent studies have revealed that codon composition in the open reading frame determines mRNA stability in multiple organisms. Based on genome‐wide correlation approaches, this previously unrecognized role for the genetic code is attributable to the kinetics of the codon‐decoding process by the ribosome. However, complementary experimental analyses are required to clarify the codon effects on mRNA stability and the related cotranslational mRNA decay pathways, for example, those triggered by aberrant ribosome stalling. In the current study, we performed a set of reporter‐based analyses to define codon‐mediated mRNA decay and ribosome stall‐dependent mRNA decay in zebrafish embryos. Our analysis showed that the effect of codons on mRNA stability stems from the decoding process, independent of the ribosome quality control factor Znf598 and stalling‐dependent mRNA decay. We propose that codon‐mediated mRNA decay is rather triggered by transiently slowed ribosomes engaging in a productive translation cycle in zebrafish embryos.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ribosome slowdown triggers codon‐mediated mRNA decay independently of ribosome quality control

et al. 2022

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“…GIGYF1/2 (orthologues to zebrafish gigyf2, Drosophila CG11148, and C. Elegans C18H9.3) regulates decay of transcripts mostly associated with secretory, membrane-bound, and actinrelated processes [232], but also of DUSP6, a negative regulator of ERK (Ras-MAPK signaling) [233]. Variants in GIGYF1/2 have been associated with both neurodegenerative and neurodevelopmental disorders in animal models and human cohorts [234,235].…”

Section: Translational Controlmentioning

confidence: 99%

Genetics, Molecular Control and Clinical Relevance of Habituation Learning

Blok¹,

Boon²,

Reijmersdal³

et al. 2022

Preprint

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Habituation, the most ancient and fundamental form of learning, manifests already before birth. Neuroscientists have been fascinated for decades by its function as a firewall protecting our brains from sensory information overload and its indispensability for higher cognitive processing. Evidence that habituation learning is affected in autism and related monogenic neurodevelopmental syndromes and their animal models has exponentially grown, but the potential of this convergence to advance both fields is still largely unexploited.In this review, we provide a systematic overview of the genes that to date have been demonstrated to underlie habituation across species. We describe the biological processes they converge on, and highlight core regulatory pathways and repurposable drugs that may alleviate the habituation deficits associated with their dysregulation. We also summarize currently used habituation paradigms and extract the most important arguments from literature that support the crucial role of habituation for cognition in health and disease. We conclude that habituation is a powerful tool to overcome current bottlenecks in research, diagnostics and treatment of neurodevelopmental disorders.

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“…GIGYF2 and ZNF598 were previously found to interact with the eIF4E‐homologous protein (4EHP) (Morita et al, 2012), which inhibits translation by competing with eIF4E for binding to the 5′‐cap structure (Rom et al, 1998). Several findings suggest that both GIGYF2‐4EHP and ZNF598 aim to minimize ribosome collisions: the translational repressor GIGYF2‐4EHP blocks new rounds of translation onto problematic mRNAs and marks these transcripts for decay whereas ZNF598 catalyzes 40S ribosomal subunit ubiquitinations required for ribosome rescue by the ribosome‐associated quality control (RQC) pathway (Hickey et al, 2020; Juszkiewicz et al, 2020; Sinha et al, 2020; Weber et al, 2020; Figure 4). In particular, ZNF598 is able to discriminate between transient or long‐lasting collisions and is essential to resolve ribosome queuing that can form on mRNAs containing ribosome stalling sequences (Goldman et al, 2021).…”

Section: The Ribosome As a Hub For Mrna Decay Quality Control And Stress Signalingmentioning

confidence: 99%

Ribosome dynamics and mRNA turnover, a complex relationship under constant cellular scrutiny

2021

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Eukaryotic gene expression is closely regulated by translation and turnover of mRNAs. Recent advances highlight the importance of translation in the control of mRNA degradation, both for aberrant and apparently normal mRNAs.During translation, the information contained in mRNAs is decoded by ribosomes, one codon at a time, and tRNAs, by specifically recognizing codons, translate the nucleotide code into amino acids. Such a decoding step does not process regularly, with various obstacles that can hinder ribosome progression, then leading to ribosome stalling or collisions. The progression of ribosomes is constantly monitored by the cell which has evolved several translationdependent mRNA surveillance pathways, including nonsense-mediated decay (NMD), no-go decay (NGD), and non-stop decay (NSD), to degrade certain problematic mRNAs and the incomplete protein products. Recent progress in sequencing and ribosome profiling has made it possible to discover new mechanisms controlling ribosome dynamics, with numerous crosstalks between translation and mRNA decay. We discuss here various translation features critical for mRNA decay, with particular focus on current insights from the complexity of the genetic code and also the emerging role for the ribosome as a regulatory hub orchestrating mRNA decay, quality control, and stress signaling. Even if the interplay between mRNA translation and degradation is no longer to be demonstrated, a better understanding of their precise coordination is worthy of further investigation.

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4EHP and GIGYF1/2 Mediate Translation-Coupled Messenger RNA Decay

Abstract: Highlights d 4EHP and GIGYF1/2 induce co-translational mRNA decay d Targeted transcripts are characterized by ribosome pausing and collision d mRNA decay requires ribosome pausing, DDX6, and partially ZNF598 d Identified mRNAs encode secreted and membrane-bound proteins or tubulin subunits

Cited by 12 publications

References 35 publications

Ribosome slowdown triggers codon‐mediated mRNA decay independently of ribosome quality control

Ribosome slowdown triggers codon‐mediated mRNA decay independently of ribosome quality control

Genetics, Molecular Control and Clinical Relevance of Habituation Learning

Ribosome dynamics and mRNA turnover, a complex relationship under constant cellular scrutiny

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