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Article ; Online: Dysfunctional tRNA reprogramming and codon-biased translation in cancer.

Dedon, Peter C / Begley, Thomas J

2022 Volume 28, Issue 11, Page(s) 964–978

Abstract: Many cancers hijack translation to increase the synthesis of tumor-driving proteins, the messenger mRNAs of which have specific codon usage patterns. Termed 'codon-biased translation' and originally identified in stress response regulation, this ... ...

Abstract	Many cancers hijack translation to increase the synthesis of tumor-driving proteins, the messenger mRNAs of which have specific codon usage patterns. Termed 'codon-biased translation' and originally identified in stress response regulation, this mechanism is supported by diverse studies demonstrating how the 50 RNA modifications of the epitranscriptome, specific tRNAs, and codon-biased mRNAs are used by oncogenic programs to promote proliferation and chemoresistance. The epitranscriptome writers METTL1-WDR4, Elongator complex protein (ELP)1-6, CTU1-2, and ALKBH8-TRM112 illustrate the principal mechanism of codon-biased translation, with gene amplifications, increased RNA modifications, and enhanced tRNA stability promoting cancer proliferation. Furthermore, systems-level analyses of 34 tRNA writers and 493 tRNA genes highlight the theme of tRNA epitranscriptome dysregulation in many cancers and identify candidate tRNA writers, tRNA modifications, and tRNA molecules as drivers of pathological codon-biased translation.
MeSH term(s)	Humans ; Codon Usage ; Protein Biosynthesis ; Codon/genetics ; RNA, Transfer/genetics ; RNA, Transfer/metabolism ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Neoplasms/genetics ; GTP-Binding Proteins/genetics ; GTP-Binding Proteins/metabolism ; AlkB Homolog 8, tRNA Methyltransferase/genetics
Chemical Substances	Codon ; RNA, Transfer (9014-25-9) ; RNA, Messenger ; WDR4 protein, human ; GTP-Binding Proteins (EC 3.6.1.-) ; ALKBH8 protein, human (EC 1.14.11.-) ; AlkB Homolog 8, tRNA Methyltransferase (EC 1.14.11.-)
Language	English
Publishing date	2022-10-11
Publishing country	England
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't
ZDB-ID	2036490-8
ISSN	1471-499X ; 1471-4914
ISSN (online)	1471-499X
ISSN	1471-4914
DOI	10.1016/j.molmed.2022.09.007
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Article ; Online: Molecular Coping Mechanisms: Reprogramming tRNAs To Regulate Codon-Biased Translation of Stress Response Proteins.

Mitchener, Michelle M / Begley, Thomas J / Dedon, Peter C

Accounts of chemical research

2023 Volume 56, Issue 23, Page(s) 3504–3514

Abstract: As part of the classic central dogma of molecular biology, transfer RNAs (tRNAs) are integral to protein translation as the adaptor molecules that link the genetic code in messenger RNA (mRNA) to the amino acids in the growing peptide chain. tRNA ... ...

Abstract	As part of the classic central dogma of molecular biology, transfer RNAs (tRNAs) are integral to protein translation as the adaptor molecules that link the genetic code in messenger RNA (mRNA) to the amino acids in the growing peptide chain. tRNA function is complicated by the existence of 61 codons to specify 20 amino acids, with most amino acids coded by two or more synonymous codons. Further, there are often fewer tRNAs with unique anticodons than there are synonymous codons for an amino acid, with a single anticodon able to decode several codons by "wobbling" of the base pairs arising between the third base of the codon and the first position on the anticodon. The complications introduced by synonymous codons and wobble base pairing began to resolve in the 1960s with the discovery of dozens of chemical modifications of the ribonucleotides in tRNA, which, by analogy to the epigenome, are now collectively referred to as the epitranscriptome for not changing the genetic code inherent to all RNA sequences. tRNA modifications were found to stabilize codon-anticodon interactions, prevent misinitiation of translation, and promote translational fidelity, among other functions, with modification deficiencies causing pathological phenotypes. This led to hypotheses that modification-dependent tRNA decoding efficiencies might play regulatory roles in cells. However, it was only with the advent of systems biology and convergent "omic" technologies that the higher level function of synonymous codons and tRNA modifications began to emerge.Here, we describe our laboratories' discovery of tRNA reprogramming and codon-biased translation as a mechanism linking tRNA modifications and synonymous codon usage to regulation of gene expression at the level of translation. Taking a historical approach, we recount how we discovered that the 8-10 modifications in each tRNA molecule undergo unique reprogramming in response to cellular stresses to promote translation of mRNA transcripts with unique codon usage patterns. These modification tunable transcripts (MoTTs) are enriched with specific codons that are differentially decoded by modified tRNAs and that fall into functional families of genes encoding proteins necessary to survive the specific stress. By developing and applying systems-level technologies, we showed that cells lacking specific tRNA modifications are sensitized to certain cellular stresses by mistranslation of proteins, disruption of mitochondrial function, and failure to translate critical stress response proteins. In essence, tRNA reprogramming serves as a cellular coping strategy, enabling rapid translation of proteins required for stress-specific cell response programs. Notably, this phenomenon has now been characterized in all organisms from viruses to humans and in response to all types of environmental changes. We also elaborate on recent findings that cancer cells hijack this mechanism to promote their own growth, metastasis, and chemotherapeutic resistance. We close by discussing how understanding of codon-biased translation in various systems can be exploited to develop new therapeutics and biomanufacturing processes.
MeSH term(s)	Humans ; Anticodon/genetics ; Codon Usage ; Protein Biosynthesis ; Heat-Shock Proteins/genetics ; Heat-Shock Proteins/metabolism ; RNA, Transfer/genetics ; RNA, Transfer/metabolism ; Codon/genetics ; Amino Acids/metabolism ; RNA, Messenger/genetics ; RNA, Messenger/metabolism
Chemical Substances	Anticodon ; Heat-Shock Proteins ; RNA, Transfer (9014-25-9) ; Codon ; Amino Acids ; RNA, Messenger
Language	English
Publishing date	2023-11-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1483291-4
ISSN	1520-4898 ; 0001-4842
ISSN (online)	1520-4898
ISSN	0001-4842
DOI	10.1021/acs.accounts.3c00572
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Article ; Online: Sulfur modification in natural RNA and therapeutic oligonucleotides.

Zheng, Ya Ying / Wu, Ying / Begley, Thomas J / Sheng, Jia

RSC chemical biology

2021 Volume 2, Issue 4, Page(s) 990–1003

Abstract: Sulfur modifications have been discovered on both DNA and RNA. Sulfur substitution of oxygen atoms at nucleobase or backbone locations in the nucleic acid framework led to a wide variety of sulfur-modified nucleosides and nucleotides. While the discovery, ...

Abstract	Sulfur modifications have been discovered on both DNA and RNA. Sulfur substitution of oxygen atoms at nucleobase or backbone locations in the nucleic acid framework led to a wide variety of sulfur-modified nucleosides and nucleotides. While the discovery, regulation and functions of DNA phosphorothioate (PS) modification, where one of the non-bridging oxygen atoms is replaced by sulfur on the DNA backbone, are important topics, this review focuses on the sulfur modification in natural cellular RNAs and therapeutic nucleic acids. The sulfur modifications on RNAs exhibit diversity in terms of modification location and cellular function, but the various sulfur modifications share common biosynthetic strategies across RNA species, cell types and domains of life. The first section reviews the post-transcriptional sulfur modifications on nucleobases with an emphasis on thiouridine on tRNA and phosphorothioate modification on RNA backbones, as well as the functions of the sulfur modifications on different species of cellular RNAs. The second section reviews the biosynthesis of different types of sulfur modifications and summarizes the general strategy for the biosynthesis of sulfur-containing RNA residues. One of the main goals of investigating sulfur modifications is to aid the genomic drug development pipeline and enhance our understandings of the rapidly growing nucleic acid-based gene therapies. The last section of the review focuses on the current drug development strategies employing sulfur substitution of oxygen atoms in therapeutic RNAs.
Language	English
Publishing date	2021-04-27
Publishing country	England
Document type	Journal Article ; Review
ISSN	2633-0679
ISSN (online)	2633-0679
DOI	10.1039/d1cb00038a
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Article: Dengue virus exploits the host tRNA epitranscriptome to promote viral replication.

Chan, Cheryl / Kwan Sze, Newman Siu / Suzuki, Yuka / Ohira, Takayuki / Suzuki, Tsutomu / Begley, Thomas J / Dedon, Peter C

bioRxiv : the preprint server for biology

2023

Abstract: The 40-50 RNA modifications of the epitranscriptome regulate posttranscriptional gene expression. Here we show that flaviviruses hijack the host tRNA epitranscriptome to promote expression of pro-viral proteins, with tRNA-modifying ALKBH1 acting as a ... ...

Abstract	The 40-50 RNA modifications of the epitranscriptome regulate posttranscriptional gene expression. Here we show that flaviviruses hijack the host tRNA epitranscriptome to promote expression of pro-viral proteins, with tRNA-modifying ALKBH1 acting as a host restriction factor in dengue virus infection. Early in the infection of human Huh-7 cells, ALKBH1 and its tRNA products 5-formylcytidine (f
Language	English
Publishing date	2023-11-06
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.11.05.565734
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Article: ROS-induced translational regulation-through spatiotemporal differences in codon recognition-is a key driver of brown adipogenesis.

Ip, Jun Yu / Wijaya, Indrik / Lee, Li Ting / Lim, Yuhua / Teoh, Deryn En-Jie / Chan, Cheryl Siew Choo / Cui, Liang / Begley, Thomas J / Dedon, Peter C / Guo, Huili

bioRxiv : the preprint server for biology

2024

Abstract: The role of translational regulation in brown adipogenesis is relatively unknown. Localized translation of mRNAs encoding mitochondrial components enables swift mitochondrial responses, but whether this occurs during brown adipogenesis, which involves ... ...

Abstract	The role of translational regulation in brown adipogenesis is relatively unknown. Localized translation of mRNAs encoding mitochondrial components enables swift mitochondrial responses, but whether this occurs during brown adipogenesis, which involves massive mitochondrial biogenesis, has not been explored. Here, we used ribosome profiling and RNA-Seq, coupled with cellular fractionation, to obtain spatiotemporal insights into translational regulation. During brown adipogenesis, a translation bias towards G/C-ending codons is triggered first in the mitochondrial vicinity by reactive oxygen species (ROS), which later spreads to the rest of the cell. This translation bias is induced through ROS modulating the activity of the tRNA modification enzyme, ELP3. Intriguingly, functionally relevant mRNAs, including those encoding ROS scavengers, benefit from this bias; in so doing, ROS-induced translation bias both fuels differentiation and concurrently minimizes oxidative damage. These ROS-induced changes could enable sustained mitochondrial biogenesis during brown adipogenesis, and explain in part, the molecular basis for ROS hormesis.
Language	English
Publishing date	2024-02-26
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.12.22.572954
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Article ; Online: Selenoproteins and the senescence-associated epitranscriptome.

Lee, May Y / Ojeda-Britez, Stephen / Ehrbar, Dylan / Samwer, Antonia / Begley, Thomas J / Melendez, J Andres

Experimental biology and medicine (Maywood, N.J.)

2022 Volume 247, Issue 23, Page(s) 2090–2102

Abstract: Selenium is a naturally found trace element, which provides multiple benefits including antioxidant, anticancer, and antiaging, as well as boosting immunity. One unique feature of selenium is its incorporation as selenocysteine, a rare 21st amino acid, ... ...

Abstract	Selenium is a naturally found trace element, which provides multiple benefits including antioxidant, anticancer, and antiaging, as well as boosting immunity. One unique feature of selenium is its incorporation as selenocysteine, a rare 21st amino acid, into selenoproteins. Twenty-five human selenoproteins have been discovered, and a majority of these serve as crucial antioxidant enzymes for redox homeostasis. Unlike other amino acids, incorporation of selenocysteine requires a distinctive UGA stop codon recoding mechanism. Although many studies correlating selenium, selenoproteins, aging, and senescence have been performed, it has not yet been explored if the upstream events regulating selenoprotein synthesis play a role in senescence-associated pathologies. The epitranscriptomic writer alkylation repair homolog 8 (ALKBH8) is critical for selenoprotein production, and its deficiency can significantly decrease levels of selenoproteins that are essential for reactive oxygen species (ROS) detoxification, and increase oxidative stress, one of the major drivers of cellular senescence. Here, we review the potential role of epitranscriptomic marks that govern selenocysteine utilization in regulating the senescence program.
MeSH term(s)	Humans ; Selenium/metabolism ; Antioxidants ; Selenocysteine/genetics ; Selenocysteine/metabolism ; Selenoproteins/genetics ; Selenoproteins/metabolism ; Codon, Terminator ; AlkB Homolog 8, tRNA Methyltransferase
Chemical Substances	Selenium (H6241UJ22B) ; Antioxidants ; Selenocysteine (0CH9049VIS) ; Selenoproteins ; Codon, Terminator ; ALKBH8 protein, human (EC 1.14.11.-) ; AlkB Homolog 8, tRNA Methyltransferase (EC 1.14.11.-)
Language	English
Publishing date	2022-08-29
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	4015-0
ISSN	1535-3699 ; 1525-1373 ; 0037-9727
ISSN (online)	1535-3699 ; 1525-1373
ISSN	0037-9727
DOI	10.1177/15353702221116592
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Article ; Online: Codon Usage and mRNA Stability are Translational Determinants of Cellular Response to Canonical Ferroptosis Inducers.

Rashad, Sherif / Byrne, Shane R / Saigusa, Daisuke / Xiang, Jingdong / Zhou, Yuan / Zhang, Liyin / Begley, Thomas J / Tominaga, Teiji / Niizuma, Kuniyasu

Neuroscience

2022 Volume 501, Page(s) 103–130

Abstract: Ferroptosis is a non-apoptotic cell death mechanism characterized by the generation of lipid peroxides. While many effectors in the ferroptosis pathway have been mapped, its epitranscriptional regulation is not yet fully understood. Ferroptosis can be ... ...

Abstract	Ferroptosis is a non-apoptotic cell death mechanism characterized by the generation of lipid peroxides. While many effectors in the ferroptosis pathway have been mapped, its epitranscriptional regulation is not yet fully understood. Ferroptosis can be induced via system xCT inhibition (Class I) or GPX4 inhibition (Class II). Previous works have revealed important differences in cellular response to different ferroptosis inducers. Importantly, blocking mRNA transcription or translation appears to protect cells against Class I ferroptosis inducing agents but not Class II. In this work, we examined the impact of blocking transcription (via Actinomycin D) or translation (via Cycloheximide) on Erastin (Class I) or RSL3 (Class II) induced ferroptosis. Blocking transcription or translation protected cells against Erastin but was detrimental against RSL3. Cycloheximide led to increased levels of GSH alone or when co-treated with Erastin via the activation of the reverse transsulfuration pathway. RNA sequencing analysis revealed early activation of a strong alternative splice program before observed changes in transcription. mRNA stability analysis revealed divergent mRNA stability changes in cellular response to Erastin or RSL3. Importantly, codon optimality biases were drastically different in either condition. Our data also implicated translation repression and rate as an important determinant of the cellular response to ferroptosis inducers. Given that mRNA stability and codon usage can be influenced via the tRNA epitranscriptome, we evaluated the role of a tRNA modifying enzyme in ferroptosis stress response. Alkbh1, a tRNA demethylase, led to translation repression and increased the resistance to Erastin but made cells more sensitive to RSL3.
MeSH term(s)	Carbolines/pharmacology ; Cell Death ; Codon Usage ; Cycloheximide ; Dactinomycin ; Ferroptosis/genetics ; Lipid Peroxides ; RNA Stability ; RNA, Messenger
Chemical Substances	Carbolines ; Lipid Peroxides ; RNA, Messenger ; Dactinomycin (1CC1JFE158) ; Cycloheximide (98600C0908)
Language	English
Publishing date	2022-08-17
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	196739-3
ISSN	1873-7544 ; 0306-4522
ISSN (online)	1873-7544
ISSN	0306-4522
DOI	10.1016/j.neuroscience.2022.08.009
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Article ; Online: The Versatile Roles of the tRNA Epitranscriptome during Cellular Responses to Toxic Exposures and Environmental Stress.

Huber, Sabrina M / Leonardi, Andrea / Dedon, Peter C / Begley, Thomas J

Toxics

2019 Volume 7, Issue 1

Abstract: Living organisms respond to environmental changes and xenobiotic exposures by regulating gene expression. While heat shock, unfolded protein, and DNA damage stress responses are well-studied at the levels of the transcriptome and proteome, tRNA-mediated ... ...

Abstract	Living organisms respond to environmental changes and xenobiotic exposures by regulating gene expression. While heat shock, unfolded protein, and DNA damage stress responses are well-studied at the levels of the transcriptome and proteome, tRNA-mediated mechanisms are only recently emerging as important modulators of cellular stress responses. Regulation of the stress response by tRNA shows a high functional diversity, ranging from the control of tRNA maturation and translation initiation, to translational enhancement through modification-mediated codon-biased translation of mRNAs encoding stress response proteins, and translational repression by stress-induced tRNA fragments. tRNAs need to be heavily modified post-transcriptionally for full activity, and it is becoming increasingly clear that many aspects of tRNA metabolism and function are regulated through the dynamic introduction and removal of modifications. This review will discuss the many ways that nucleoside modifications confer high functional diversity to tRNAs, with a focus on tRNA modification-mediated regulation of the eukaryotic response to environmental stress and toxicant exposures. Additionally, the potential applications of tRNA modification biology in the development of early biomarkers of pathology will be highlighted.
Language	English
Publishing date	2019-03-25
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2733883-6
ISSN	2305-6304 ; 2305-6304
ISSN (online)	2305-6304
ISSN	2305-6304
DOI	10.3390/toxics7010017
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Article ; Online: Loss of epitranscriptomic control of selenocysteine utilization engages senescence and mitochondrial reprogramming

Lee, May Y / Leonardi, Andrea / Begley, Thomas J / Melendez, J Andrés

Redox biology

2019 Volume 28, Page(s) 101375

Abstract: Critically important to the maintenance of the glutathione (GSH) redox cycle are the activities of many selenocysteine-containing GSH metabolizing enzymes whose translation is controlled by the epitranscriptomic writer alkylation repair homolog 8 (ALKBH8) ...

Abstract	Critically important to the maintenance of the glutathione (GSH) redox cycle are the activities of many selenocysteine-containing GSH metabolizing enzymes whose translation is controlled by the epitranscriptomic writer alkylation repair homolog 8 (ALKBH8). ALKBH8 is a tRNA methyltransferase that methylates the wobble uridine of specific tRNAs to regulate the synthesis of selenoproteins. Here we demonstrate that a deficiency in the writer ALKBH8 (Alkbh8
MeSH term(s)	AlkB Homolog 8, tRNA Methyltransferase/genetics ; Animals ; Cells, Cultured ; Cellular Senescence ; Epigenesis, Genetic ; Gene Deletion ; Gene Expression Profiling/methods ; Humans ; Mice ; Mitochondria/metabolism ; Oxygen Consumption ; Selenocysteine/metabolism ; Uncoupling Protein 2/metabolism
Chemical Substances	Uncoupling Protein 2 ; Selenocysteine (0CH9049VIS) ; ALKBH8 protein, human (EC 1.14.11.-) ; ALKBH8 protein, mouse (EC 1.14.11.-) ; AlkB Homolog 8, tRNA Methyltransferase (EC 1.14.11.-)
Language	English
Publishing date	2019-11-11
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2701011-9
ISSN	2213-2317 ; 2213-2317
ISSN (online)	2213-2317
ISSN	2213-2317
DOI	10.1016/j.redox.2019.101375
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Article: Translational response to mitochondrial stresses is orchestrated by tRNA modifications.

Rashad, Sherif / Al-Mesitef, Shadi / Mousa, Abdulrahman / Zhou, Yuan / Ando, Daisuke / Sun, Guangxin / Fukuuchi, Tomoko / Iwasaki, Yuko / Xiang, Jingdong / Byrne, Shane R / Sun, Jingjing / Maekawa, Masamitsu / Saigusa, Daisuke / Begley, Thomas J / Dedon, Peter C / Niizuma, Kuniyasu

bioRxiv : the preprint server for biology

2024

Abstract: Mitochondrial stress and dysfunction play important roles in many pathologies. However, how cells respond to mitochondrial stress is not fully understood. Here, we examined the translational response to electron transport chain (ETC) inhibition and ... ...

Abstract	Mitochondrial stress and dysfunction play important roles in many pathologies. However, how cells respond to mitochondrial stress is not fully understood. Here, we examined the translational response to electron transport chain (ETC) inhibition and arsenite induced mitochondrial stresses. Our analysis revealed that during mitochondrial stress, tRNA modifications (namely f5C, hm5C, queuosine and its derivatives, and mcm5U) dynamically change to fine tune codon decoding, usage, and optimality. These changes in codon optimality drive the translation of many pathways and gene sets, such as the ATF4 pathway and selenoproteins, involved in the cellular response to mitochondrial stress. We further examined several of these modifications using targeted approaches. ALKBH1 knockout (KO) abrogated f5C and hm5C levels and led to mitochondrial dysfunction, reduced proliferation, and impacted mRNA translation rates. Our analysis revealed that tRNA queuosine (tRNA-Q) is a master regulator of the mitochondrial stress response. KO of QTRT1 or QTRT2, the enzymes responsible for tRNA-Q synthesis, led to mitochondrial dysfunction, translational dysregulation, and metabolic alterations in mitochondria-related pathways, without altering cellular proliferation. In addition, our analysis revealed that tRNA-Q loss led to a domino effect on various tRNA modifications. Some of these changes could be explained by metabolic profiling. Our analysis also revealed that utilizing serum deprivation or alteration with Queuine supplementation to study tRNA-Q or stress response can introduce various confounding factors by altering many other tRNA modifications. In summary, our data show that tRNA modifications are master regulators of the mitochondrial stress response by driving changes in codon decoding.
Language	English
Publishing date	2024-02-14
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.02.14.580389
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