tRNA Modifications and Modifying Enzymes in Disease, the Potential Therapeutic Targets

Cui, Weifang; Zhao, Delong; Jiang, Jinbao; Tang, Faqing; Zhang, Chunfang; Duan, Chaojun

doi:10.7150/ijbs.80233

Cited by 18 publications

(11 citation statements)

References 178 publications

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“…As for tRNAs, they are a kind of ncRNA that play a key role during protein translation [ 42 ]. An expanding body of empirical evidence has substantiated the association between tRNA modification and tumor progression.…”

Section: Diagnosis and Survival Prognosismentioning

confidence: 99%

Clinical Significance of Non-Coding RNA Regulation of Programmed Cell Death in Hepatocellular Carcinoma

Chen,

Ruan,

Zou

et al. 2023

Cancers

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Hepatocellular carcinoma (HCC) is a widely prevalent and malignantly progressive tumor. Most patients are typically diagnosed with HCC at an advanced stage, posing significant challenges in the execution of curative surgical interventions. Non-coding RNAs (ncRNAs) represent a distinct category of RNA molecules not directly involved in protein synthesis. However, they possess the remarkable ability to regulate gene expression, thereby exerting significant regulatory control over cellular processes. Notably, ncRNAs have been implicated in the modulation of programmed cell death (PCD), a crucial mechanism that various therapeutic agents target in the fight against HCC. This review summarizes the clinical significance of ncRNA regulation of PCD in HCC, including patient diagnosis, prognosis, drug resistance, and side effects. The aim of this study is to provide new insights and directions for the diagnosis and drug treatment strategies of HCC.

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Section: Diagnosis and Survival Prognosismentioning

confidence: 99%

Clinical Significance of Non-Coding RNA Regulation of Programmed Cell Death in Hepatocellular Carcinoma

Chen,

Ruan,

Zou

et al. 2023

Cancers

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“…tRNAs are the most heavily modified cellular RNA, with more than 100 known modifications, modulating protein folding, stability, and function (19)(20)(21)(22)(23)(24)(25)(26). Increasing links between mutations in tRNAs and neurological disease highlight the importance of understanding tRNA processing and function in the context of the nervous system (15)(16)(17)(18)(27)(28)(29)(30)(31). However, it remains unclear why disruption of tRNA biogenesis and function disproportionately affects the nervous system, underscoring the need for further investigation.…”

Section: Introductionmentioning

confidence: 99%

tRNA modification enzyme-dependent redox homeostasis regulates synapse formation and memory

Madhwani,

Sayied,

Ogata

et al. 2023

Preprint

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Post-transcriptional modification of RNA regulates gene expression at multiple levels. ALKBH8 is a tRNA modifying enzyme that methylates wobble uridines in specific tRNAs to modulate translation. Through methylation of tRNA-selenocysteine, ALKBH8 promotes selenoprotein synthesis and regulates redox homeostasis. Pathogenic variants in ALKBH8 have been linked to intellectual disability disorders in the human population, but the role of ALKBH8 in the nervous system is unknown. Throughin vivostudies inDrosophila, we show that ALKBH8 controls oxidative stress in the brain to restrain synaptic growth and support learning and memory.ALKBH8null animals lack wobble uridine methylation and exhibit a global reduction in protein synthesis, including a specific decrease in selenoprotein levels. Loss ofALKBH8or independent disruption of selenoprotein synthesis results in ectopic synapse formation. Genetic expression of antioxidant enzymes fully suppresses synaptic overgrowth inALKBH8null animals, confirming oxidative stress as the underlying cause of dysregulation.ALKBH8animals also exhibit associative learning and memory impairments that are reversed by pharmacological antioxidant treatment. Together, these findings demonstrate the critical role of tRNA modification in redox homeostasis in the nervous system and reveal antioxidants as a potential therapy for ALKBH8-associated intellectual disability.Significance StatementtRNA modifying enzymes are emerging as important regulators of nervous system development and function due to their growing links to neurological disorders. Yet, their roles in the nervous system remain largely elusive. Throughin vivostudies inDrosophila, we link tRNA methyltransferase-regulated selenoprotein synthesis to synapse development and associative memory. These findings demonstrate the key role of tRNA modifiers in redox homeostasis during nervous system development and highlight the potential therapeutic benefit of antioxidant-based therapies for cognitive disorders linked to dysregulation of tRNA modification.

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“…Importantly, the dysregulation of tRNA modifications has been implicated in a host of human diseases known as tRNA modopathies. 9 mRNAs also contain multiple different types of modifications, 6 and more recent studies have illuminated the importance of modifications such as N 6 methyladenosine (m 6 A), pseudouridine (ψ), and inosine (I), among others, in mRNA biology.…”

Section: Introductionmentioning

confidence: 99%

“…Although tRNA modifications have been better studied than modifications on other types of RNA, most investigation has been performed in model organisms such as E. coli and yeast, and the homologous mammalian tRNA modifications and tRNA-modifying enzymes are still relatively poorly characterized. Importantly, the dysregulation of tRNA modifications has been implicated in a host of human diseases known as tRNA modopathies . mRNAs also contain multiple different types of modifications, and more recent studies have illuminated the importance of modifications such as N 6 -methyladenosine (m 6 A), pseudouridine (ψ), and inosine (I), among others, in mRNA biology.…”

Section: Introductionmentioning

confidence: 99%

Chemoproteomic Approaches to Studying RNA Modification-Associated Proteins

Dai,

Yu,

Kleiner

2023

Acc. Chem. Res.

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Conspectus The function of cellular RNA is modulated by a host of post-transcriptional chemical modifications installed by dedicated RNA-modifying enzymes. RNA modifications are widespread in biology, occurring in all kingdoms of life and in all classes of RNA molecules. They regulate RNA structure, folding, and protein–RNA interactions, and have important roles in fundamental gene expression processes involving mRNA, tRNA, rRNA, and other types of RNA species. Our understanding of RNA modifications has advanced considerably; however, there are still many outstanding questions regarding the distribution of modifications across all RNA transcripts and their biological function. One of the major challenges in the study of RNA modifications is the lack of sequencing methods for the transcriptome-wide mapping of different RNA-modification structures. Furthermore, we lack general strategies to characterize RNA-modifying enzymes and RNA-modification reader proteins. Therefore, there is a need for new approaches to enable integrated studies of RNA-modification chemistry and biology. In this Account, we describe our development and application of chemoproteomic strategies for the study of RNA-modification-associated proteins. We present two orthogonal methods based on nucleoside and oligonucleotide chemical probes: 1) RNA-mediated activity-based protein profiling (RNABPP), a metabolic labeling strategy based on reactive modified nucleoside probes to profile RNA-modifying enzymes in cells and 2) photo-cross-linkable diazirine-containing synthetic oligonucleotide probes for identifying RNA-modification reader proteins. We use RNABPP with C5-modified cytidine and uridine nucleosides to capture diverse RNA-pyrimidine-modifying enzymes including methyltransferases, dihydrouridine synthases, and RNA dioxygenase enzymes. Metabolic labeling facilitates the mechanism-based cross-linking of RNA-modifying enzymes with their native RNA substrates in cells. Covalent RNA–protein complexes are then isolated by denaturing oligo(dT) pulldown, and cross-linked proteins are identified by quantitative proteomics. Once suitable modified nucleosides have been identified as mechanism-based proteomic probes, they can be further deployed in transcriptome-wide sequencing experiments to profile the substrates of RNA-modifying enzymes at nucleotide resolution. Using 5-fluorouridine-mediated RNA–protein cross-linking and sequencing, we analyzed the substrates of human dihydrouridine synthase DUS3L. 5-Ethynylcytidine-mediated cross-linking enabled the investigation of ALKBH1 substrates. We also characterized the functions of these RNA-modifying enzymes in human cells by using genetic knockouts and protein translation reporters. We profiled RNA readers for N 6-methyladenosine (m6A) and N 1-methyladenosine (m1A) using a comparative proteomic workflow based on diazirine-containing modified oligonucleotide probes. Our approach enables quantitative proteome-wide analysis of the preference of RNA-binding proteins for modified nucleotides across a range of...

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tRNA Modifications and Modifying Enzymes in Disease, the Potential Therapeutic Targets

Cited by 18 publications

References 178 publications

Clinical Significance of Non-Coding RNA Regulation of Programmed Cell Death in Hepatocellular Carcinoma

Clinical Significance of Non-Coding RNA Regulation of Programmed Cell Death in Hepatocellular Carcinoma

tRNA modification enzyme-dependent redox homeostasis regulates synapse formation and memory

Chemoproteomic Approaches to Studying RNA Modification-Associated Proteins

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