Disrupting tRNA modifications to target mitochondrial vulnerabilities in drug-resistant leukemia cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE228208 | GEO | 2025/08/19
REPOSITORIES: GEO
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Project description:Disrupting tRNA modifications to target mitochondrial vulnerabilities in drug-resistant leukemia cells
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Project description:Diverse chemical modifications fine-tune the function and metabolism of tRNA. Although tRNA modification is universal in all kingdoms of life, profiles of modifications, their functions, and physiological roles have not been elucidated in most organisms including the human pathogen, Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis. To identify physiologically important modifications, we surveyed the tRNA of Mtb, using tRNA sequencing (tRNA-seq). Reverse transcription-derived error signatures in tRNA-seq predicted the sites and presence of 9 modifications. Several chemical treatments prior to tRNA-seq expanded the number of predictable modifications. Deletion of Mtb genes encoding two modifying enzymes, TruB and MnmA, eliminated their respective tRNA modifications, validating the presence of modified sites in tRNA species.
2023-08-11 | GSE240200 | GEO
Project description:Abstract: tRNAs are highly modified in the elbow region and harbor 5-methyluridine at position 54 and pseudouridine at position 55 in the T arm, which are generated by the enzymes TrmA and TruB, respectively. Although all elongator tRNAs contain these modifications across all domains of life, the cellular relevance of these modifications and their corresponding modifying enzymes remains elusive. In addition to modifying every tRNA, Escherichia coli TrmA and TruB have both been shown to fold tRNA independently of its modification activity acting as tRNA chaperones, and strains lacking trmA or truB are outcompeted by wildtype. To identify how TrmA and TruB contribute to cellular fitness, we have systematically assessed the effects of deleting trmA and/or trmB in E. coli. Since tRNA folding is a pre-requisite for tRNA aminoacylation, we determined cellular aminoacylation levels revealing a global decrease in aminoacylation for all tRNAs in ΔtrmA and ΔtruB. Moreover, the absence of 5-methyluridine 54 or pseudouridine 55 alters tRNA modification at other positions: whereas acp3U47 is decreased, thiouridine levels are increased. Understanding the importance of TrmA and TruB for tRNA aminoacylation and modification, we then analyzed how these global tRNA changes in ΔtrmA and ΔtruB strains affect translation. Whereas global protein synthesis is not significantly changed in ΔtrmA and ΔtruB, the abundances of many specific proteins are altered, and transcriptomics experiments suggest that the dysregulation of many proteins is controlled at the translational level. In conclusion, we demonstrate that universally conserved modifications of the tRNA elbow are critical for global tRNA function by enhancing other tRNA modifications, tRNA folding, tRNA aminoacylation and translation of specific genes thereby contributing to cellular fitness.
2023-05-31 | GSE233667 | GEO
Project description:The chloroplast is a promising platform for biotechnological innovation due to its compact translation machinery. Nucleotide modifications within a minimal set of tRNAs modulate codon-anticodon interactions that are crucial for translation efficiency. However, a comprehensive assessment of these modifications does not presently exist in chloroplasts. Here, we synthesize all available information concerning tRNA modifications in the chloroplast and assign translation efficiency for each modified anticodon-codon pair. In addition, we perform a bioinformatics analysis that links enzymes to tRNA modifications and aminoacylation in the chloroplast of Chlamydomonas reinhardtii. This work provides the first comprehensive analysis of codon and anticodon interactions of chloroplasts and its implication for translation efficiency.
| S-EPMC8877259 | biostudies-literature
Project description:Transfer RNA (tRNA) modifications are essential for the temperature adaptation of thermophilic and psychrophilic organisms as they control the rigidity and flexibility of transcripts. To further understand how specific tRNA modifications are adjusted to maintain functionality in response to temperature fluctuations, we investigated whether tRNA modifications represent an adaptation of bacteria to different growth temperatures (minimal, optimal, and maximal), focusing on closely related psychrophilic (P. halocryophilus and E. sibiricum), mesophilic (B. subtilis), and thermophilic (G. stearothermophilus) Bacillales. Utilizing an RNA sequencing approach combined with chemical pre-treatment of tRNA samples, we systematically profiled dihydrouridine (D), 4-thiouridine (s4U), 7-methyl-guanosine (m7G), and pseudouridine (Ψ) modifications at single-nucleotide resolution. Despite their close relationship, each bacterium exhibited a unique tRNA modification profile. Our findings revealed increased tRNA modifications in the thermophilic bacterium at its optimal growth temperature, particularly showing elevated levels of s4U8 and Ψ55 modifications compared to non-thermophilic bacteria, indicating a temperature-dependent regulation that may contribute to thermotolerance. Furthermore, we observed higher levels of D modifications in psychrophilic and mesophilic bacteria, indicating an adaptive strategy for cold environments by enhancing local flexibility in tRNAs. Our method demonstrated high effectiveness in identifying tRNA modifications compared to an established tool, highlighting its potential for precise tRNA profiling studies.
| S-EPMC11354880 | biostudies-literature
Project description:Chemical modifications of the nucleosides that comprise transfer RNAs are diverse. However, the structure, location and extent of modifications have been systematically charted in very few organisms. Here, we describe an approach in which rapid prediction of modified sites through reverse transcription-derived signatures in high-throughput transfer RNA-sequencing (tRNA-seq) data is coupled with identification of tRNA modifications through RNA mass spectrometry. Comparative tRNA-seq enabled prediction of several Vibrio cholerae modifications that are absent from Escherichia coli and also revealed the effects of various environmental conditions on V. cholerae tRNA modification. Through RNA mass spectrometric analyses, we showed that two of the V. cholerae-specific reverse transcription signatures reflected the presence of a new modification (acetylated acp3U (acacp3U)), while the other results from C-to-Ψ RNA editing, a process not described before. These findings demonstrate the utility of this approach for rapid surveillance of tRNA modification profiles and environmental control of tRNA modification.
| S-EPMC8172280 | biostudies-literature
Project description:More than 90 different modified nucleosides have been identified in tRNA. Among the tRNA modifications, the 7-methylguanosine (m⁷G) modification is found widely in eubacteria, eukaryotes, and a few archaea. In most cases, the m⁷G modification occurs at position 46 in the variable region and is a product of tRNA (m⁷G46) methyltransferase. The m⁷G46 modification forms a tertiary base pair with C13-G22, and stabilizes the tRNA structure. A reaction mechanism for eubacterial tRNA m⁷G methyltransferase has been proposed based on the results of biochemical, bioinformatic, and structural studies. However, an experimentally determined mechanism of methyl-transfer remains to be ascertained. The physiological functions of m⁷G46 in tRNA have started to be determined over the past decade. For example, tRNA m⁷G46 or tRNA (m⁷G46) methyltransferase controls the amount of other tRNA modifications in thermophilic bacteria, contributes to the pathogenic infectivity, and is also associated with several diseases. In this review, information of tRNA m⁷G modifications and tRNA m⁷G methyltransferases is summarized and the differences in reaction mechanism between tRNA m⁷G methyltransferase and rRNA or mRNA m⁷G methylation enzyme are discussed.
| S-EPMC6320965 | biostudies-literature
Project description:BackgroundIn past number of methods have been developed for predicting post-translational modifications in proteins. In contrast, limited attempt has been made to understand post-transcriptional modifications. Recently it has been shown that tRNA modifications play direct role in the genome structure and codon usage. This study is an attempt to understand kingdom-wise tRNA modifications particularly uridine modifications (UMs), as majority of modifications are uridine-derived.ResultsA three-steps strategy has been applied to develop an efficient method for the prediction of UMs. In the first step, we developed a common prediction model for all the kingdoms using a dataset from MODOMICS-2008. Support Vector Machine (SVM) based prediction models were developed and evaluated by five-fold cross-validation technique. Different approaches were applied and found that a hybrid approach of binary and structural information achieved highest Area under the curve (AUC) of 0.936. In the second step, we used newly added tRNA sequences (as independent dataset) of MODOMICS-2012 for the kingdom-wise prediction performance evaluation of previously developed (in the first step) common model and achieved performances between the AUC of 0.910 to 0.949. In the third and last step, we used different datasets from MODOMICS-2012 for the kingdom-wise individual prediction models development and achieved performances between the AUC of 0.915 to 0.987.ConclusionsThe hybrid approach is efficient not only to predict kingdom-wise modifications but also to classify them into two most prominent UMs: Pseudouridine (Y) and Dihydrouridine (D). A webserver called tRNAmod (http://crdd.osdd.net/raghava/trnamod/) has been developed, which predicts UMs from both tRNA sequences and whole genome.
| S-EPMC4287530 | biostudies-literature
Project description:Transfer RNAs (tRNAs) are essential adaptors that mediate translation of the genetic code. These molecules undergo a variety of post-transcriptional modifications, which expand their chemical reactivity while influencing their structure, stability, and functionality. Chemical modifications to tRNA ensure translational competency and promote cellular viability. Hence, the placement and prevalence of tRNA modifications affects the efficiency of aminoacyl tRNA synthetase (aaRS) reactions, interactions with the ribosome, and transient pairing with messenger RNA (mRNA). The synthesis and abundance of tRNA modifications respond directly and indirectly to a range of environmental and nutritional factors involved in the maintenance of metabolic homeostasis. The dynamic landscape of the tRNA epitranscriptome suggests a role for tRNA modifications as markers of cellular status and regulators of translational capacity. This review discusses the non-canonical roles that tRNA modifications play in central metabolic processes and how their levels are modulated in response to a range of cellular demands.
| S-EPMC7466049 | biostudies-literature
Project description:tRNAs constitute the most highly modified class of RNA. Every tRNA contains a unique set of modifications, and Ψ55, m5U54, and m7G46 are frequently found within the elbow of the tRNA structure. Despite the abundance of tRNA modifications, we are only beginning to understand the orchestration of modification enzymes during tRNA maturation. Here, we investigated whether pre-existing modifications impact the binding affinity or catalysis by tRNA elbow modification enzymes. Specifically, we focused on the Escherichia coli enzymes TruB, TrmA, and TrmB which generate Ψ55, m5U54, and m7G46, respectively. tRNAs containing a single modification were prepared, and the binding and activity preferences of purified E. coli TrmA, TruB, and TrmB were examined in vitro. TruB preferentially binds and modifies unmodified tRNA. TrmA prefers to modify unmodified tRNA, but binds most tightly to tRNA that already contains Ψ55. In contrast, binding and modification by TrmB is insensitive to the tRNA modification status. Our results suggest that TrmA and TruB are likely to act on mostly unmodified tRNA precursors during the early stages of tRNA maturation whereas TrmB presumably acts on later tRNA intermediates that are already partially modified. In conclusion, we uncover the mechanistic basis for the preferred modification order in the E. coli tRNA elbow region.
| S-EPMC7430675 | biostudies-literature