Epitranscriptomic Code and Its Alterations in Human Disease

Kadumuri, Rajashekar Varma; Janga, Sarath Chandra

doi:10.1016/j.molmed.2018.07.010

Cited by 116 publications

(133 citation statements)

References 146 publications

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“…Many recent studies have demonstrated that RNA undergoes various modifications in a manner similar to DNA. These RNA modifications play a role in many cellular and biological processes, thereby opening up an emerging research field known as epitranscriptomics [1][2][3][4][5][6][7] . According to the MODOMICS database,~170 different RNA modifications have been identified in coding and noncoding RNAs 5,8,9 .…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…These RNA modifications can affect a variety of molecular processes, such as transcription, pre-mRNA splicing, RNA export, mRNA translation, and RNA degradation 1,[3][4][5][6][7] . All of these molecular events contribute to shaping the cellular transcriptome and proteome [1][2][3][4][5][6][7]13 . In particular, recent reports have posited that the regulation of mRNA stability through RNA modification is a crucial step for the tight regulation of gene expression [1][2][3][4][5][6][7]13 .…”

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: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

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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“…It represents one of the first examples of how a mammalian RNA modification system is vital after environmental challenge. As there are over twenty epitranscriptomic writers in mammals (Kadumuri & Janga, 2018), there are most likely other RNA modifications, writers and perhaps erasers essential to the response to common environmental toxicants.…”

Section: Discussionmentioning

confidence: 99%

Epitranscriptomic regulation of the response to the air pollutant naphthalene in mouse lungs: from the perspectives of specialized translation and tolerance linked to the writer ALKBH8

Leonardi

Kovalchuk

Yin

et al. 2019

Preprint

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Background:The epitranscriptomic writer Alkylation Repair Homolog 8 (ALKBH8) is a tRNA methyltransferase that modifies the wobble uridine of selenocysteine tRNA to promote the specialized translation, via stop codon recoding, of proteins that contain selenocysteine. Corresponding selenoproteins play critical roles in protecting against reactive oxygen species and environmental stress. Using a novel animal model deficient in Alkbh8, we have investigated the importance of epitranscriptomic systems in the response to naphthalene (NA), an abundant polycyclic aromatic hydrocarbon, glutathione depleter and lung toxicant found in tobacco smoke, gasoline and mothballs.Objectives: Our goal was to define the molecular reprogramming of Alkbh8 deficient (Alkbh8 def ) mice and evaluate the roles that the epitranscriptomic writer ALKBH8 and selenoproteins play in mitigating NA-induced toxicity and lung dysfunction. Methods:We performed basal lung analysis and NA exposure studies using WT, Alkbh8 def and Cyp2abfgs-null mice, the latter of which lack the cytochrome P450 enzymes required for NA bioactivation. We characterized gene expression, molecular markers of damage, viability and tolerance to NA.Results: Under basal conditions, lungs from Alkbh8 def mice have increased oxidationreduction potential (ORP) and 8-isoprostane levels, and have reprogrammed at the molecular level to display increased stress response transcripts. In addition, the ALKBH8 writer deficient lungs have a decreased GSH/GSSG ratio. Alkbh8 def mice are more sensitive to NA than WT, showing higher susceptibility to lung damage both at the cellular and molecular levels. WT mice develop a tolerance to NA after 3 days, defined as resistance to a high challenging dose after repeated exposures, which is absent in Alkbh8 def mice, with writer deficient not surviving NA exposure. Discussion:We conclude that the epitranscriptomic writer ALKBH8 plays a protective role against NA-induced lung dysfunction and promotes NA tolerance. Our work provides an early example of how epitranscriptomic systems can regulate the response to environmental stress in vivo.

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“…Alterations in the expression levels of few RNA modifiers of tRNA and rRNA have been linked to cancer as well as other human diseases [17][18][19][20]. However, the consequences of changes affecting the core machinery of protein translation are rarely explained.…”

Section: Introductionmentioning

confidence: 99%

Disruption of the RNA modifications that target the ribosome translation machinery in human cancer

2020

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Genetic and epigenetic changes deregulate RNA and protein expression in cancer cells. In this regard, tumors exhibit an abnormal proteome in comparison to the corresponding normal tissues. Translation control is a crucial step in the regulation of gene expression regulation under normal and pathological conditions that ultimately determines cellular fate. In this context, evidence shows that transfer and ribosomal RNA (tRNA and rRNA) modifications affect the efficacy and fidelity of translation. The number of RNA modifications increases with the complexity of organisms, suggesting an evolutionary diversification of the possibilities for fine-tuning the functions of coding and non-coding RNAs. In this review, we focus on alterations of modifications of transfer and ribosomal RNA that affect translation in human cancer. This variation in the RNA modification status can be the result of altered modifier expression (writers, readers or erasers), but also due to components of the machineries (C/D or H/ ACA boxes) or alterations of proteins involved in modifier expression. Broadening our understanding of the mechanisms by which site-specific modifications modulate ribosome activity in the context of tumorigenesis will enable us to enrich our knowledge about how ribosomes can influence cell fate and form the basis of new therapeutic opportunities.

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Epitranscriptomic Code and Its Alterations in Human Disease

Cited by 116 publications

References 146 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

Epitranscriptomic regulation of the response to the air pollutant naphthalene in mouse lungs: from the perspectives of specialized translation and tolerance linked to the writer ALKBH8

Disruption of the RNA modifications that target the ribosome translation machinery in human cancer

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