Loss of Elp1 in cerebellar granule cell progenitors models ataxia phenotype of Familial Dysautonomia DOI Creative Commons

Frederik Arnskötter,

Patricia Benites Goncalves da Silva,

Mackenna E. Schouw

и другие.

Neurobiology of Disease, Год журнала: 2024, Номер 199, С. 106600 - 106600

Опубликована: Июль 11, 2024

Familial Dysautonomia (FD) is an autosomal recessive disorder caused by a splice site mutation in the gene ELP1, which disproportionally affects neurons. While classically characterized deficits sensory and autonomic neurons, neuronal defects central nervous system have also been described. Although ELP1 expression remains high normal developing adult cerebellum, its role cerebellar development unknown. To explore of Elp1 we knocked out granule cell progenitors (GCPs) examined outcome on animal behavior cellular composition. We found that GCP-specific conditional knockout (Elp1

Язык: Английский

Human TRMT1 and TRMT1L paralogs ensure the proper modification state, stability, and function of tRNAs DOI
Kejia Zhang, Aidan C. Manning, Jenna M. Lentini

и другие.

Cell Reports, Год журнала: 2025, Номер 44(1), С. 115092 - 115092

Опубликована: Янв. 1, 2025

Язык: Английский

Процитировано

6
tRNA therapeutics for genetic diseases DOI
Jeff Coller, Zoya Ignatova

Nature Reviews Drug Discovery, Год журнала: 2023, Номер 23(2), С. 108 - 125

Опубликована: Дек. 4, 2023

Язык: Английский

Процитировано

33
Comparative analysis of 43 distinct RNA modifications by nanopore tRNA sequencing DOI Creative Commons
Laura K. White,

Kezia Dobson,

Samantha del Pozo

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июль 24, 2024

Abstract Transfer RNAs are the fundamental adapter molecules of protein synthesis and most abundant heterogeneous class noncoding RNA in cells. The study tRNA repertoires remains challenging, complicated by presence dozens post transcriptional modifications. Nanopore sequencing is an emerging technology with promise for both detection modifications; however, such studies have been limited throughput accuracy direct methods. Moreover, complete set modifications nanopore challenging. Here we show that recent updates to chemistry (RNA004) combined our own optimizations protocols analysis workflows enable high coverage characterization signals produced 43 distinct We share best practices further report successful low abundance mitochondrial viral tRNAs, providing proof concept use populations context infection organelle biology. This work provides a roadmap guide future efforts towards de novo across multiple organisms using sequencing.

Язык: Английский

Процитировано

9
Cell-type-specific expression of tRNAs in the brain regulates cellular homeostasis DOI Creative Commons

Mridu Kapur,

Michael J. Molumby,

Carlos Guzman

и другие.

Neuron, Год журнала: 2024, Номер 112(9), С. 1397 - 1415.e6

Опубликована: Фев. 19, 2024

Defects in tRNA biogenesis are associated with multiple neurological disorders, yet our understanding of these diseases has been hampered by an inability to determine expression individual cell types within a complex tissue. Here, we developed mouse model which RNA polymerase III is conditionally epitope tagged Cre-dependent manner, allowing us accurately profile any type vivo. We investigated diverse nervous system types, revealing dramatic heterogeneity the genes between populations. found that while maintenance levels isoacceptor families critical for cellular homeostasis, neurons differentially vulnerable insults distinct families. Cell-type-specific translatome analysis suggests balance availability and codon demand may underlie such differential resilience. Our work provides platform investigating complexities mRNA translation biology brain.

Язык: Английский

Процитировано

7
Understanding the role of tRNA modifications in UGA recoding as selenocysteine in eukaryotes DOI
Laurent Chavatte,

L F De Lange,

Ulrich Schweizer

и другие.

Journal of Molecular Biology, Год журнала: 2025, Номер unknown, С. 169017 - 169017

Опубликована: Фев. 1, 2025

Язык: Английский

Процитировано

1
The Evolution and Implications of the Inosine tRNA Modification DOI Creative Commons
Peter T. S. van der Gulik, Wouter D. Hoff

Journal of Molecular Biology, Год журнала: 2025, Номер unknown, С. 169187 - 169187

Опубликована: Май 1, 2025

Ever since the legendary publication by Francis Crick in JMB introducing wobble hypothesis 1966, inosine has been a permanent part of molecular biology. This review aims to integrate rich array novel insights emerging from subsequent research on adenine-to-inosine modification tRNA, with an emphasis results obtained during last 5 years. Both grand panorama 4 billion years evolution life and medical implications defects will be reviewed. The most salient are that: (1) at position 34 (the first anticodon) is not universally present tree life; (2) many bacteria just single homodimeric enzyme (TadA) responsible for both tRNA mRNA modification; (3) rapid progress currently being made understanding heterodimeric ADAT2/ADAT3 modifications eukaryotes experimental capabilities monitoring cytoplasmic pool their modifications; (4) selected tRNAs, 37 demonstrated but this remains under-studied; (5) tRNAs known contain can incomplete; (6) GC content T-stem great importance behavior, including wobbling behavior inosine; (7) direct relevance human disease. In summary, continues yield important insights.

Язык: Английский

Процитировано

1
Disease association and therapeutic routes of aminoacyl-tRNA synthetases DOI
Ina Yoon,

Uijoo Kim,

Jae Young Choi

и другие.

Trends in Molecular Medicine, Год журнала: 2023, Номер 30(1), С. 89 - 105

Опубликована: Ноя. 8, 2023

Язык: Английский

Процитировано

13
tRNA modification enzyme-dependent redox homeostasis regulates synapse formation and memory DOI Creative Commons
Kimberly R. Madhwani, Shanzeh Sayied, Carlson H. Ogata

и другие.

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(46)

Опубликована: Ноя. 4, 2024

Post-transcriptional modification of RNA regulates gene expression at multiple levels. ALKBH8 is a tRNA-modifying enzyme that methylates wobble uridines in subset tRNAs to modulate translation. Through methylation tRNA-selenocysteine, promotes selenoprotein synthesis and redox homeostasis. Pathogenic variants have been linked intellectual disability disorders the human population, but role nervous system unknown. vivo studies Drosophila , we show controls oxidative stress brain restrain synaptic growth support learning memory. null animals lack uridine exhibit reduced protein system, including specific decrease Either loss or independent disruption results ectopic synapse formation. Genetic antioxidant enzymes fully suppresses overgrowth animals, confirming as underlying cause dysregulation. also associative memory impairments are reversed by pharmacological treatment. Together, these findings demonstrate critical tRNA homeostasis developing reveal antioxidants potential therapy for ALKBH8-associated disability.

Язык: Английский

Процитировано

5
Strategies for Detecting Aminoacylation and Aminoacyl‐tRNA Editing In Vitro and In Cells DOI Creative Commons

Rylan R. Watkins,

Arundhati Kavoor,

Karin Musier‐Forsyth

и другие.

Israel Journal of Chemistry, Год журнала: 2024, Номер unknown

Опубликована: Май 6, 2024

Aminoacyl-tRNA synthetases (aaRSs) maintain translational fidelity by ensuring the formation of correct aminoacyl-tRNA pairs. Numerous point mutations in human aaRSs have been linked to disease phenotypes. Structural studies from pathogens encoding unique domains support these enzymes as potential candidates for therapeutics. Studies shown that identity tRNA pools cells changes between different cell types and under stress conditions. While traditional radioactive aminoacylation analyses can determine effect disease-causing on aaRS function, assays are not amenable drug discovery campaigns do take into account variability intracellular pools. Here, we review modern techniques characterize activity vitro cells. The cell-based approaches analyse pool observe trends fidelity. Taken together, allow high-throughput screening inhibitors systems-level dynamic population a variety conditions states.

Язык: Английский

Процитировано

4
tRNA and tsRNA: From Heterogeneity to Multifaceted Regulators DOI Creative Commons
Yun Li,

Zongyu Yu,

Wen‐An Jiang

и другие.

Biomolecules, Год журнала: 2024, Номер 14(10), С. 1340 - 1340

Опубликована: Окт. 21, 2024

As the most ancient RNA, transfer RNAs (tRNAs) play a more complex role than their constitutive function as amino acid transporters in protein synthesis process. The transcription and maturation of tRNA cells are subject to stringent regulation, resulting formation tissue- cell-specific pools with variations overall abundance, composition, modification, charging levels. heterogeneity contributes facilitating histocyte-specific expression patterns is involved diverse biological processes. Moreover, tRNAs can be recognized by various RNase under physiological pathological conditions generate tRNA-derived small (tsRNAs) serve regulatory Here, we summarize these recent insights into highlight advances regulation tsRNA biogenesis modifications. We synthesize mechanisms embryonic development, cell fate determination, epigenetic inheritance regulation. also discuss potential clinical applications based on new knowledge diagnostic prognostic biomarkers therapeutic strategies for multiple diseases.

Язык: Английский

Процитировано

4