Oxidation and alkylation stresses activate ribosome-quality control

Yan, Liewei L.; Simms, Carrie L.; McLoughlin, Fionn; Vierstra, Richard D.; Zaher, Hani

doi:10.1038/s41467-019-13579-3

Cited by 92 publications

(83 citation statements)

References 94 publications

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“…As a result, numerous alkylated nucleosides can be generated in RNA, possibly affecting the RNA structure and/or the protein-coding potential of mRNA. A recent study even showed that alkylated mRNA is subject to rapid degradation via NGD 12 . Finally, the presence of internal N 7methylguanosine (m 7 G) in mRNA is known to promote translation.…”

Section: Discussionmentioning

confidence: 99%

“…The oxidation of mRNA affects multiple steps of mRNA fate determination, including mRNA stability and translation 12,[70][71][72][73] . For instance, the oxidation of mRNA (typically 8-oxoG) inhibits the efficiency of peptide bond formation by >1000-fold, regardless of the codon position 71 .…”

Section: -Oxo-78-dihydroguanosinementioning

confidence: 99%

“…1) 1,3-7 : (i) writer proteins (RNAmodifying enzymes), which transfer a specific chemical group to a target position on an RNA molecule; (ii) RNAbinding proteins (RBPs), which specifically recognize the modified nucleotides (reader proteins); and (iii) eraser proteins, which remove specific chemical groups from the modified nucleotides, converting them back into unmodified nucleotides. In certain cases, endogenous or exogenous chemical damage can also generate RNA modifications without the involvement of writer proteins 11,12 . In addition, some modifications are reversible, while others are irreversible.…”

Section: Introductionmentioning

confidence: 99%

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The emerging role of RNA modifications in the regulation of mRNA stability

2020

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Many studies have highlighted the importance of the tight regulation of mRNA stability in the control of gene expression. mRNA stability largely depends on the mRNA nucleotide sequence, which affects the secondary and tertiary structures of the mRNAs, and the accessibility of various RNA-binding proteins to the mRNAs. Recent advances in high-throughput RNA-sequencing techniques have resulted in the elucidation of the important roles played by mRNA modifications and mRNA nucleotide sequences in regulating mRNA stability. To date, hundreds of different RNA modifications have been characterized. Among them, several RNA modifications, including N 6-methyladenosine (m 6 A), N 6 ,2′-O-dimethyladenosine (m 6 Am), 8-oxo-7,8-dihydroguanosine (8-oxoG), pseudouridine (Ψ), 5-methylcytidine (m 5 C), and N 4-acetylcytidine (ac 4 C), have been shown to regulate mRNA stability, consequently affecting diverse cellular and biological processes. In this review, we discuss our current understanding of the molecular mechanisms underlying the regulation of mammalian mRNA stability by various RNA modifications.

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Section: Discussionmentioning

confidence: 99%

Section: -Oxo-78-dihydroguanosinementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The emerging role of RNA modifications in the regulation of mRNA stability

2020

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“…As mentioned before, oxidative stress can impact translation at several steps of the process, including initiation, elongation, and quality control [50,164,165]. Recent work by the Zaher lab showed that RNA alkylating and oxidizing agents, MMS and 4-NQO, respectively, can lead to ribosome stalling and increased Ltn1-dependent ubiquitination of the arrested peptide, in addition to ubiquitination of ribosomal proteins mediated by the RQC E3 Hel2 [194]. Therefore, RTU and RQC pathways seem to be important to control specific subpopulations of ribosomes that might arise depending on the intensity of the stress, its duration, and the chemical nature of the reactive oxygen species employed.…”

Section: Overview Of Redox Control Of Translation By Ubiquitin (Rtu) mentioning

confidence: 96%

Expanding Role of Ubiquitin in Translational Control

Dougherty

Maduka

Inada

et al. 2020

IJMS

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The eukaryotic proteome has to be precisely regulated at multiple levels of gene expression, from transcription, translation, and degradation of RNA and protein to adjust to several cellular conditions. Particularly at the translational level, regulation is controlled by a variety of RNA binding proteins, translation and associated factors, numerous enzymes, and by post-translational modifications (PTM). Ubiquitination, a prominent PTM discovered as the signal for protein degradation, has newly emerged as a modulator of protein synthesis by controlling several processes in translation. Advances in proteomics and cryo-electron microscopy have identified ubiquitin modifications of several ribosomal proteins and provided numerous insights on how this modification affects ribosome structure and function. The variety of pathways and functions of translation controlled by ubiquitin are determined by the various enzymes involved in ubiquitin conjugation and removal, by the ubiquitin chain type used, by the target sites of ubiquitination, and by the physiologic signals triggering its accumulation. Current research is now elucidating multiple ubiquitin-mediated mechanisms of translational control, including ribosome biogenesis, ribosome degradation, ribosome-associated protein quality control (RQC), and redox control of translation by ubiquitin (RTU). This review discusses the central role of ubiquitin in modulating the dynamism of the cellular proteome and explores the molecular aspects responsible for the expanding puzzle of ubiquitin signals and functions in translation.Int. J. Mol. Sci. 2020, 21, 1151 2 of 24 initiation, elongation, and termination, with each being fundamental processes conserved across all organisms [20][21][22]. These steps require the proper binding of both RNA and protein factors, and regulation is often facilitated by the alteration of these binding patterns. As ribosomes are highly abundant and responsible for all protein synthesis within the cell, even minor changes to binding patterns could have a large impact on global protein production and cellular health, depending on which steps of translation are altered. Mutations and dysregulation of translational control can lead to a variety of diseases such as cancer, neurological disorders, bone marrow dysfunction and immunodeficiency, among others [23]. As translation is a core process in maintaining cellular function and health, dysfunctional regulation can have devastating results for the cell.Translational control does not occur in a universal manner across a single cell, but varies based on ribosomal subpopulations, with functions specific to cellular localization, transcript targeting, and signaling pathways [24,25]. These subpopulations are distinguishable by RNA and ribosomal protein composition [26,27], binding factors [28], intracellular localization [29,30], and post-translational modifications (PTM) [31]. These subpopulations have a differential capacity to bind and interact with both mRNA and protein factors required for active transla...

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“…Oxidative modifications of mRNA can also impair base pairing within RNA and are capable of triggering ribosome quality control pathways [156]. Although oxidized mRNAs can recruit the translation apparatus for decoding, they eventually cause synthesis of erroneous protein products and premature translation termination in rabbit reticulocyte lysate and human HEK-293 cells [157].…”

Section: Mrnas and Trnasmentioning

confidence: 99%

Effects of Oxidative Stress on Protein Translation: Implications for Cardiovascular Diseases

Ghosh

Shcherbik

2020

IJMS

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Cardiovascular diseases (CVDs) are a group of disorders that affect the heart and blood vessels. Due to their multifactorial nature and wide variation, CVDs are the leading cause of death worldwide. Understanding the molecular alterations leading to the development of heart and vessel pathologies is crucial for successfully treating and preventing CVDs. One of the causative factors of CVD etiology and progression is acute oxidative stress, a toxic condition characterized by elevated intracellular levels of reactive oxygen species (ROS). Left unabated, ROS can damage virtually any cellular component and affect essential biological processes, including protein synthesis. Defective or insufficient protein translation results in production of faulty protein products and disturbances of protein homeostasis, thus promoting pathologies. The relationships between translational dysregulation, ROS, and cardiovascular disorders will be examined in this review.

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Oxidation and alkylation stresses activate ribosome-quality control

Cited by 92 publications

References 94 publications

The emerging role of RNA modifications in the regulation of mRNA stability

The emerging role of RNA modifications in the regulation of mRNA stability

Expanding Role of Ubiquitin in Translational Control

Effects of Oxidative Stress on Protein Translation: Implications for Cardiovascular Diseases

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