AMD1 mRNA employs ribosome stalling as a mechanism for molecular memory formation

Yordanova, Martina M.; Loughran, Gary; Zhdanov, Alexander V.; Mariotti, Marco; Kiniry, Stephen J; O‘Connor, Patrick B F; Andreev, Dmitry E.; Tzani, Ioanna; Saffert, Paul; Michel, Audrey M.; Gladyshev, Vadim N.; Papkovsky, Dmitry B; Atkins, John F.; Baranov, Pavel V.

doi:10.1038/nature25174

Cited by 67 publications

(74 citation statements)

References 40 publications

(35 reference statements)

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“…Improved experimental and analytical methods for transcriptome‐wide analysis of translation have been essential for identifying hitherto unprecedented mechanisms of translation regulation (Truitt & Ruggero, ; Ingolia et al , ; Yordanova et al , ). Using such methods, upon depletion of ERα in prostate cancer, we observed that translational offsetting appears to be a pervasive mechanism which maintains proteome composition.…”

Section: Discussionmentioning

confidence: 99%

Translational offsetting as a mode of estrogen receptor α‐dependent regulation of gene expression

et al. 2019

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Estrogen receptor alpha (ERα) activity is associated with increased cancer cell proliferation. Studies aiming to understand the impact of ERα on cancer‐associated phenotypes have largely been limited to its transcriptional activity. Herein, we demonstrate that ERα coordinates its transcriptional output with selective modulation of mRNA translation. Importantly, translational perturbations caused by depletion of ERα largely manifest as “translational offsetting” of the transcriptome, whereby amounts of translated mRNAs and corresponding protein levels are maintained constant despite changes in mRNA abundance. Transcripts whose levels, but not polysome association, are reduced following ERα depletion lack features which limit translation efficiency including structured 5′UTRs and miRNA target sites. In contrast, mRNAs induced upon ERα depletion whose polysome association remains unaltered are enriched in codons requiring U34‐modified tRNAs for efficient decoding. Consistently, ERα regulates levels of U34‐modifying enzymes and thereby controls levels of U34‐modified tRNAs. These findings unravel a hitherto unprecedented mechanism of ERα‐dependent orchestration of transcriptional and translational programs that may be a pervasive mechanism of proteome maintenance in hormone‐dependent cancers.

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Section: Discussionmentioning

confidence: 99%

Translational offsetting as a mode of estrogen receptor α‐dependent regulation of gene expression

et al. 2019

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“…The downregulation of protein expression associated with 3′‐UTR translation has been reported in nematodes , mice , and humans , suggesting the existence of quality control mechanisms to repress aberrant C‐terminally extended proteins produced by translation of the 3′‐UTRs. A recent study showed that translation of the 3′‐UTR of human AMD1 ( S ‐adenosylmethionine decarboxylase proenzyme) causes ribosome arrest in an amino acid sequence‐dependent manner . Ribosome arrest at the 3′‐UTR leads to queuing of ribosomes on the mRNA, thereby repressing translation.…”

mentioning

confidence: 95%

Translation arrest as a protein quality control system for aberrant translation of the 3′‐UTR in mammalian cells

et al. 2019

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Read‐through or mutations of a stop codon resulting in translation of the 3′‐UTR produce potentially toxic C‐terminally extended proteins. However, quality control mechanisms for such proteins are poorly understood in mammalian cells. Here, a comprehensive analysis of the 3′‐UTRs of genes associated with hereditary diseases identified novel arrest‐inducing sequences in the 3′‐UTRs of 23 genes that can repress the levels of their protein products. In silico analysis revealed that the hydrophobicity of the polypeptides encoded in the 3′‐UTRs is correlated with arrest efficiency. These results provide new insight into quality control mechanisms mediated by 3′‐UTRs to prevent the production of C‐terminally extended cytotoxic proteins.

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“…Recently, a short sequence capable of inducing ribosome stalling was described in an ORF located at the 3′UTR of adenosylmethionine decarboxylase 1 (AMD1) mRNA [43]. This sequence does not terminate in NPG (Fig.…”

Section: Stalling By Non-viral Peptides Encoded In the Human Genomementioning

confidence: 99%

BiP/GRP78 Mediates ERAD Targeting of Proteins Produced by Membrane-Bound Ribosomes Stalled at the STOP-Codon

Cesaratto

Sasset

Myers

et al. 2019

Journal of Molecular Biology

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Translational stalling of ribosome bound to endoplasmic reticulum (ER) membrane requires an accurate clearance of the associated polypeptides, which is not completely understood in mammals. We characterized in mammalian cells the model of ribosomal stalling at the STOP-codon based on proteins tagged at the C-terminus with the picornavirus 2A peptide followed by a termination codon instead of the Proline (2A*). We exploited the 2A* stalling model to characterize the pathway of degradation of ER-targeted polypeptides. We report that the ER chaperone BiP/GRP78 is a new main factor involved. Moreover, degradation of the ER-stalled polypeptides required the activities of the AAA-ATPase VCP/p97, its associated deubiquitinylase YOD1, the ribosome-associated ubiquitin ligase Listerin and the proteasome. In human proteome, we found two human C-terminal amino acid sequences that cause similar stalling at the STOP-codon. Our data suggest that translational stalling at the ER membrane activates protein degradation at the interface of ribosomal-and ERassociated quality control systems.

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AMD1 mRNA employs ribosome stalling as a mechanism for molecular memory formation

Cited by 67 publications

References 40 publications

Translational offsetting as a mode of estrogen receptor α‐dependent regulation of gene expression

Translational offsetting as a mode of estrogen receptor α‐dependent regulation of gene expression

Translation arrest as a protein quality control system for aberrant translation of the 3′‐UTR in mammalian cells

BiP/GRP78 Mediates ERAD Targeting of Proteins Produced by Membrane-Bound Ribosomes Stalled at the STOP-Codon

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