The Branched Nature of the Nonsense-Mediated mRNA Decay Pathway

Yi, Zhongxia; Sanjeev, Manu; Singh, Guramrit

doi:10.1016/j.tig.2020.08.010

Cited by 63 publications

(54 citation statements)

References 151 publications

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“…Conversely, the cap-and poly(A)-binding proteins eIF4E and PABPC1, as well as translation initiation factors such as EIF4A1, EIF4A2, EIF4B, EIF4G1, and EIF4G3, are present in cluster 2, which is composed of upregulated RBPs (Figures 3A and 3B; Table S4). These opposing results support a model in which the cap-and poly(A)-binding factors can interact with cellular mRNAs but cannot associate with EIF3 and the ribosomal subunit 40S, which agrees with the reported action of NSP1 preventing 40S recruitment to cellular mRNAs (Gehring et al, 2009;Schubert et al, 2020;Tidu et al, 2020;Yi et al, 2021).…”

Section: Ll Open Accesssupporting

confidence: 89%

“…If this model is correct, it is expected that the exon junction complex (EJC) would accumulate onto cellular mRNAs, because it is removed during the pioneering round of translation (Gehring et al, 2009;Yi et al, 2021). To test this hypothesis, we searched for the core components of the EJC in our dataset and observed that EIF4A3, RBM8A, and CASC3 are upregulated in SARS-CoV-2-infected cells (also in cluster 2) (Figures 3A, 3B, and S3E).…”

Section: Ll Open Accessmentioning

confidence: 99%

“…Deposition of EJCs on cellular RNAs is a consequence of the splicing reaction (Yi et al, 2021). However, a recent study reported that NSP16 interacts with the U1 and U2 small nuclear RNAs (snRNAs) and disrupts splicing (Banerjee et al, 2020).…”

Section: Ll Open Accessmentioning

confidence: 99%

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Global analysis of protein-RNA interactions in SARS-CoV-2-infected cells reveals key regulators of infection

et al. 2021

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19. SARS-CoV-2 relies on cellular RNA-binding proteins (RBPs) to replicate and spread, although which RBPs control its life cycle remains largely unknown. Here, we employ a multi-omic approach to identify systematically and comprehensively the cellular and viral RBPs that are involved in SARS-CoV-2 infection. We reveal that SARS-CoV-2 infection profoundly remodels the cellular RNA-bound proteome, which includes wide-ranging effects on RNA metabolic pathways, non-canonical RBPs and antiviral factors. Moreover, we apply a new method to identify the proteins that directly interact with viral RNA, uncovering dozens of cellular RBPs and six viral proteins. Amongst them, several components of the tRNA ligase complex, which we show regulate SARS-CoV-2 infection. Furthermore, we discover that available drugs targeting host RBPs that interact with SARS-CoV-2 RNA inhibit infection. Collectively, our results uncover a new universe of host-virus interactions with potential for new antiviral therapies against COVID-19.

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Section: Ll Open Accesssupporting

confidence: 89%

Section: Ll Open Accessmentioning

confidence: 99%

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Global analysis of protein-RNA interactions in SARS-CoV-2-infected cells reveals key regulators of infection

et al. 2021

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“…The idea that the mammalian NMD pathway consists of multiple branches with distinct factor requirements and substrate specificities has been proposed by several groups, but the underlying mechanisms and regulatory roles of NMD branching are poorly understood (Huang et al , 2011; Chan et al , 2007; Yi et al , 2020). Our identification of differential activities of UPF1 SL and UPF1 LL is an unforeseen example of NMD pathway branching, which can be controlled at the cellular level by changes in the abundance of protective RBPs, translation, or UPF1 splicing.…”

Section: Discussionmentioning

confidence: 99%

An alternative UPF1 isoform drives conditional remodeling of nonsense-mediated mRNA decay

Fritz

Ranganathan

Wang

et al. 2021

Preprint

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The nonsense-mediated mRNA decay (NMD) pathway monitors translation termination to degrade transcripts with premature stop codons and regulate thousands of human genes. Due to the major role of NMD in RNA quality control and gene expression regulation, it is important to understand how the pathway responds to changing cellular conditions. Here we show that an alternative mammalian-specific isoform of the core NMD factor UPF1, termed UPF1LL, enables condition-dependent remodeling of NMD specificity. UPF1LL associates more stably with potential NMD target mRNAs than the major UPF1SL isoform, expanding the scope of NMD to include many transcripts normally immune to the pathway. Unexpectedly, the enhanced persistence of UPF1LL on mRNAs supports induction of NMD in response to rare translation termination events. Thus, while canonical NMD is abolished by translational repression, UPF1LL activity is enhanced, providing a mechanism to rapidly rewire NMD specificity in response to cellular stress.

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“…Importantly, the isoform containing the 5’SS at +2 results in a frame-shift with a stop codon in the 3’UTR of the RPL11 canonical transcript. Thus, this isoform is unlikely to be an NMD substrate due to an absence of early stop codon upstream of any intron [14]. This alternative RPL11 isoform when translated shares the first 134 amino acids with the canonical RPL11 protein ( Figure 2B ).…”

Section: Resultsmentioning

confidence: 99%

Loss of coordinated expression between ribosomal and mitochondrial genes revealed by comprehensive characterization of a large family with a rare mendelian disorder

Panici

Nakajima

Carlston³

et al. 2020

Preprint

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Variants that perturb splicing are major contributors to disease. Recent evidence implicate non-canonical intronic variants as a poorly characterized yet highly prevalent class of alterations associated with Mendelian disorders. Here, we report the first detailed RNA expression and splicing analysis from a large family with an intronic RPL11 variant associated with Diamond Blackfan Anemia (DBA). DBA manifests with incomplete penetrance and partial expressivity yet the mechanism of this variability remains enigmatic. Our analysis revealed a complex pattern of disruptions with many novel junctions of RPL11. These include an RPL11 transcript that is translated with a late stop codon in the 3' untranslated region (3'UTR) of the main isoform and an antisense exon-exon junction variant present only in carriers. We observed that RPL11 transcript abundance is comparable among carriers regardless of symptom severity. In contrast, both the small and large ribosomal subunit transcripts were significantly overexpressed in individuals with more prominent DBA symptoms. Finally, we discovered that coordinated expression between mitochondrial components and RPL11 was lost in all carriers, which may lead to variable expressivity. Overall, this study highlights the importance of RNA splicing and expression analyses in families for molecular characterization of Mendelian diseases.

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The Branched Nature of the Nonsense-Mediated mRNA Decay Pathway

Cited by 63 publications

References 151 publications

Global analysis of protein-RNA interactions in SARS-CoV-2-infected cells reveals key regulators of infection

Global analysis of protein-RNA interactions in SARS-CoV-2-infected cells reveals key regulators of infection

An alternative UPF1 isoform drives conditional remodeling of nonsense-mediated mRNA decay

Loss of coordinated expression between ribosomal and mitochondrial genes revealed by comprehensive characterization of a large family with a rare mendelian disorder

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