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Article ; Online: Landscape of semi-extractable RNAs across five human cell lines.

Zeng, Chao / Chujo, Takeshi / Hirose, Tetsuro / Hamada, Michiaki

2023 Volume 51, Issue 15, Page(s) 7820–7831

Abstract: Phase-separated membraneless organelles often contain RNAs that exhibit unusual semi-extractability using the conventional RNA extraction method, and can be efficiently retrieved by needle shearing or heating during RNA extraction. Semi-extractable RNAs ... ...

Abstract	Phase-separated membraneless organelles often contain RNAs that exhibit unusual semi-extractability using the conventional RNA extraction method, and can be efficiently retrieved by needle shearing or heating during RNA extraction. Semi-extractable RNAs are promising resources for understanding RNA-centric phase separation. However, limited assessments have been performed to systematically identify and characterize semi-extractable RNAs. In this study, 1074 semi-extractable RNAs, including ASAP1, DANT2, EXT1, FTX, IGF1R, LIMS1, NEAT1, PHF21A, PVT1, SCMH1, STRG.3024.1, TBL1X, TCF7L2, TVP23C-CDRT4, UBE2E2, ZCCHC7, ZFAND3 and ZSWIM6, which exhibited consistent semi-extractability were identified across five human cell lines. By integrating publicly available datasets, we found that semi-extractable RNAs tend to be distributed in the nuclear compartments but are dissociated from the chromatin. Long and repeat-containing semi-extractable RNAs act as hubs to provide global RNA-RNA interactions. Semi-extractable RNAs were divided into four groups based on their k-mer content. The NEAT1 group preferred to interact with paraspeckle proteins, such as FUS and NONO, implying that RNAs in this group are potential candidates of architectural RNAs that constitute nuclear bodies.
MeSH term(s)	Humans ; Cell Line ; Cell Nucleus/metabolism ; Chromatin/metabolism ; DNA-Binding Proteins/genetics ; RNA/isolation & purification ; RNA, Long Noncoding/genetics ; RNA, Long Noncoding/metabolism
Chemical Substances	Chromatin ; DNA-Binding Proteins ; RNA (63231-63-0) ; RNA, Long Noncoding
Language	English
Publishing date	2023-07-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkad567
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Article ; Online: Human transfer RNA modopathies: diseases caused by aberrations in transfer RNA modifications.

Chujo, Takeshi / Tomizawa, Kazuhito

The FEBS journal

2021 Volume 288, Issue 24, Page(s) 7096–7122

Abstract: tRNA molecules are post-transcriptionally modified by tRNA modification enzymes. Although composed of different chemistries, more than 40 types of human tRNA modifications play pivotal roles in protein synthesis by regulating tRNA structure and stability ...

Abstract	tRNA molecules are post-transcriptionally modified by tRNA modification enzymes. Although composed of different chemistries, more than 40 types of human tRNA modifications play pivotal roles in protein synthesis by regulating tRNA structure and stability as well as decoding genetic information on mRNA. Many tRNA modifications are conserved among all three kingdoms of life, and aberrations in various human tRNA modification enzymes cause life-threatening diseases. Here, we describe the class of diseases and disorders caused by aberrations in tRNA modifications as 'tRNA modopathies'. Aberrations in over 50 tRNA modification enzymes are associated with tRNA modopathies, which most frequently manifest as dysfunctions of the brain and/or kidney, mitochondrial diseases, and cancer. However, the molecular mechanisms that link aberrant tRNA modifications to human diseases are largely unknown. In this review, we provide a comprehensive compilation of human tRNA modification functions, tRNA modification enzyme genes, and tRNA modopathies, and we summarize the elucidated pathogenic mechanisms underlying several tRNA modopathies. We will also discuss important questions that need to be addressed in order to understand the molecular pathogenesis of tRNA modopathies.
MeSH term(s)	Brain Diseases/metabolism ; Brain Diseases/pathology ; Humans ; Kidney Diseases/metabolism ; Kidney Diseases/pathology ; Mitochondrial Diseases/metabolism ; Mitochondrial Diseases/pathology ; RNA Processing, Post-Transcriptional/genetics ; RNA, Transfer/genetics ; RNA, Transfer/metabolism
Chemical Substances	RNA, Transfer (9014-25-9)
Language	English
Publishing date	2021-02-16
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2173655-8
ISSN	1742-4658 ; 1742-464X
ISSN (online)	1742-4658
ISSN	1742-464X
DOI	10.1111/febs.15736
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Article: Human transfer RNA modopathies: diseases caused by aberrations in transfer RNA modifications

Chujo, Takeshi / Tomizawa, Kazuhito

FEBS journal. 2021 Dec., v. 288, no. 24

2021

Abstract: tRNA molecules are post‐transcriptionally modified by tRNA modification enzymes. Although composed of different chemistries, more than 40 types of human tRNA modifications play pivotal roles in protein synthesis by regulating tRNA structure and stability ...

Abstract	tRNA molecules are post‐transcriptionally modified by tRNA modification enzymes. Although composed of different chemistries, more than 40 types of human tRNA modifications play pivotal roles in protein synthesis by regulating tRNA structure and stability as well as decoding genetic information on mRNA. Many tRNA modifications are conserved among all three kingdoms of life, and aberrations in various human tRNA modification enzymes cause life‐threatening diseases. Here, we describe the class of diseases and disorders caused by aberrations in tRNA modifications as ‘tRNA modopathies’. Aberrations in over 50 tRNA modification enzymes are associated with tRNA modopathies, which most frequently manifest as dysfunctions of the brain and/or kidney, mitochondrial diseases, and cancer. However, the molecular mechanisms that link aberrant tRNA modifications to human diseases are largely unknown. In this review, we provide a comprehensive compilation of human tRNA modification functions, tRNA modification enzyme genes, and tRNA modopathies, and we summarize the elucidated pathogenic mechanisms underlying several tRNA modopathies. We will also discuss important questions that need to be addressed in order to understand the molecular pathogenesis of tRNA modopathies.
Keywords	brain ; enzymes ; humans ; kidneys ; mitochondria ; pathogenesis ; protein synthesis ; transfer RNA
Language	English
Dates of publication	2021-12
Size	p. 7096-7122.
Publishing place	John Wiley & Sons, Ltd
Document type	Article
Note	REVIEW
ZDB-ID	2173655-8
ISSN	1742-4658 ; 1742-464X
ISSN (online)	1742-4658
ISSN	1742-464X
DOI	10.1111/febs.15736
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Article ; Online: Nuclear Bodies Built on Architectural Long Noncoding RNAs: Unifying Principles of Their Construction and Function.

Chujo, Takeshi / Hirose, Tetsuro

Molecules and cells

2017 Volume 40, Issue 12, Page(s) 889–896

Abstract: Nuclear bodies are subnuclear, spheroidal, and membraneless compartments that concentrate specific proteins and/or RNAs. They serve as sites of biogenesis, storage, and sequestration of specific RNAs, proteins, or ribonucleoprotein complexes. Recent ... ...

Abstract	Nuclear bodies are subnuclear, spheroidal, and membraneless compartments that concentrate specific proteins and/or RNAs. They serve as sites of biogenesis, storage, and sequestration of specific RNAs, proteins, or ribonucleoprotein complexes. Recent studies reveal that a subset of nuclear bodies in various eukaryotic organisms is constructed using architectural long noncoding RNAs (arcRNAs). Here, we describe the unifying mechanistic principles of the construction and function of these bodies, especially focusing on liquid-liquid phase separation induced by architectural molecules that form multiple weakly adhesive interactions. We also discuss three possible advantages of using arcRNAs rather than architectural proteins to build the bodies: position-specificity, rapidity, and economy in sequestering nucleic acid-binding proteins. Moreover, we introduce two recently devised methods to discover novel arcRNA-constructed bodies; one that focuses on the RNase-sensitivity of these bodies, and another that focuses on "semi-extractability" of arcRNAs.
MeSH term(s)	Cell Nucleus/metabolism ; Humans ; RNA, Long Noncoding/genetics ; RNA, Long Noncoding/metabolism
Chemical Substances	RNA, Long Noncoding
Language	English
Publishing date	2017-12-20
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1148964-9
ISSN	0219-1032 ; 1016-8478
ISSN (online)	0219-1032
ISSN	1016-8478
DOI	10.14348/molcells.2017.0263
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Article ; Online: Remarkable improvement in detection of readthrough downstream-of-gene transcripts by semi-extractable RNA-sequencing.

Iwakiri, Junichi / Tanaka, Kumiko / Chujo, Takeshi / Takakuwa, Hiro / Yamazaki, Tomohiro / Terai, Goro / Asai, Kiyoshi / Hirose, Tetsuro

RNA (New York, N.Y.)

2022 Volume 29, Issue 2, Page(s) 170–177

Abstract: The mammalian cell nucleus contains dozens of membrane-less nuclear bodies that play significant roles in various aspects of gene expression. Several nuclear bodies are nucleated by specific architectural noncoding RNAs (arcRNAs) acting as structural ... ...

Abstract	The mammalian cell nucleus contains dozens of membrane-less nuclear bodies that play significant roles in various aspects of gene expression. Several nuclear bodies are nucleated by specific architectural noncoding RNAs (arcRNAs) acting as structural scaffolds. We have reported that a minor population of cellular RNAs exhibits an unusual semi-extractable feature upon using the conventional procedure of RNA preparation and that needle shearing or heating of cell lysates remarkably improves extraction of dozens of RNAs. Because semi-extractable RNAs, including known arcRNAs, commonly localize in nuclear bodies, this feature may be a hallmark of arcRNAs. Using the semi-extractability of RNA, we performed genome-wide screening of semi-extractable long noncoding RNAs to identify new candidate arcRNAs for arcRNA under hyperosmotic and heat stress conditions. After screening stress-inducible and semi-extractable RNAs, hundreds of readthrough downstream-of-gene (DoG) transcripts over several hundreds of kilobases, many of which were not detected among RNAs prepared by the conventional extraction procedure, were found to be stress-inducible and semi-extractable. We further characterized some of the abundant DoGs and found that stress-inducible transient extension of the 3'-UTR made DoGs semi-extractable. Furthermore, they were localized in distinct nuclear foci that were sensitive to 1,6-hexanediol. These data suggest that semi-extractable DoGs exhibit arcRNA-like features and our semi-extractable RNA-seq is a powerful tool to extensively monitor DoGs that are induced under specific physiological conditions.
MeSH term(s)	Animals ; Base Sequence ; Cell Nucleus/metabolism ; RNA, Untranslated/genetics ; RNA, Untranslated/metabolism ; RNA, Long Noncoding/genetics ; RNA, Long Noncoding/metabolism ; Mammals/genetics
Chemical Substances	RNA, Untranslated ; RNA, Long Noncoding
Language	English
Publishing date	2022-11-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1241540-6
ISSN	1469-9001 ; 1355-8382
ISSN (online)	1469-9001
ISSN	1355-8382
DOI	10.1261/rna.079469.122
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Article ; Online: Export of RNA-derived modified nucleosides by equilibrative nucleoside transporters defines the magnitude of autophagy response and Zika virus replication

Shi, Sheng-Lan / Fukuda, Hiroyuki / Chujo, Takeshi / Kouwaki, Takahisa / Oshiumi, Hiroyuki / Tomizawa, Kazuhito / Wei, Fan-Yan

RNA Biology. 2021 Oct. 15, v. 18, no. S1 p.478-495

2021

Abstract: RNA contains a wide variety of posttranscriptional modifications covalently attached to its base or sugar group. These modified nucleosides are liberated from RNA molecules as the consequence of RNA catabolism and released into extracellular space, but ... ...

Abstract	RNA contains a wide variety of posttranscriptional modifications covalently attached to its base or sugar group. These modified nucleosides are liberated from RNA molecules as the consequence of RNA catabolism and released into extracellular space, but the molecular mechanism of extracellular transport and its pathophysiological implications have been unclear. In the present study, we discovered that RNA-derived modified nucleosides are exported to extracellular space through equilibrative nucleoside transporters 1 and 2 (ENT1 and ENT2), with ENT1 showing higher preference for modified nucleosides than ENT2. Pharmacological inhibition or genetic deletion of ENT1 and ENT2 significantly attenuated export of modified nucleosides thereby resulting in their accumulation in cytosol. Using mutagenesis strategy, we identified an amino acid residue in ENT1 that is involved in the discrimination of unmodified and modified nucleosides. In ENTs-deficient cells, the elevated levels of intracellular modified nucleosides were closely associated with an induction of autophagy response as evidenced by increased LC3-II level. Importantly, we performed a screening of modified nucleosides capable of inducing autophagy and found that 1-methylguanosine (m¹G) was sufficient to induce LC3-II levels. Pathophysiologically, defective export of modified nucleosides drastically induced Zika virus replication in an autophagy-dependent manner. In addition, we also found that pharmacological inhibition of ENTs by dilazep significantly induced Zika virus replication. Collectively, our findings highlight RNA-derived modified nucleosides as important signaling modulators that activate autophagy response and indicate that defective export of these modified nucleoside can have profound consequences for pathophysiology.
Keywords	RNA ; Zika virus ; amino acids ; autophagy ; catabolism ; chemical bonding ; cytosol ; exports ; extracellular space ; mutagenesis ; nucleosides ; pathophysiology ; sugars ; virus replication ; RNA modification ; nucleoside transport ; equilibrative nucleoside transporter ; virus infection
Language	English
Dates of publication	2021-1015
Size	p. 478-495.
Publishing place	Taylor & Francis
Document type	Article ; Online
ZDB-ID	2159587-2
ISSN	1555-8584
ISSN	1555-8584
DOI	10.1080/15476286.2021.1960689
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Article ; Online: NSUN3-mediated mitochondrial tRNA 5-formylcytidine modification is essential for embryonic development and respiratory complexes in mice.

Murakami, Yoshitaka / Wei, Fan-Yan / Kawamura, Yoshimi / Horiguchi, Haruki / Kadomatsu, Tsuyoshi / Miyata, Keishi / Miura, Kyoko / Oike, Yuichi / Ando, Yukio / Ueda, Mitsuharu / Tomizawa, Kazuhito / Chujo, Takeshi

Communications biology

2023 Volume 6, Issue 1, Page(s) 307

Abstract: In mammalian mitochondria, translation of the AUA codon is supported by 5-formylcytidine ( ... ...

Abstract	In mammalian mitochondria, translation of the AUA codon is supported by 5-formylcytidine (f
MeSH term(s)	Humans ; Animals ; Mice ; Adult ; Anticodon ; RNA, Transfer, Met/genetics ; Codon ; Mitochondria/genetics ; Mammals/genetics ; Methyltransferases/genetics
Chemical Substances	Anticodon ; 5-formylcytidine (148608-53-1) ; RNA, Transfer, Met ; Codon ; NSUN3 protein, human (EC 2.1.1.-) ; Methyltransferases (EC 2.1.1.-)
Language	English
Publishing date	2023-03-22
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-023-04680-x
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Article ; Online: Pathological mutations promote proteolysis of mitochondrial tRNA-specific 2-thiouridylase 1 (MTU1) via mitochondrial caseinolytic peptidase (CLPP).

Ahmad, Raja Norazireen Raja / Zhang, Long-Teng / Morita, Rikuri / Tani, Haruna / Wu, Yong / Chujo, Takeshi / Ogawa, Akiko / Harada, Ryuhei / Shigeta, Yasuteru / Tomizawa, Kazuhito / Wei, Fan-Yan

Nucleic acids research

2023 Volume 52, Issue 3, Page(s) 1341–1358

Abstract: MTU1 controls intramitochondrial protein synthesis by catalyzing the 2-thiouridine modification of mitochondrial transfer RNAs (mt-tRNAs). Missense mutations in the MTU1 gene are associated with life-threatening reversible infantile hepatic failure. ... ...

Abstract	MTU1 controls intramitochondrial protein synthesis by catalyzing the 2-thiouridine modification of mitochondrial transfer RNAs (mt-tRNAs). Missense mutations in the MTU1 gene are associated with life-threatening reversible infantile hepatic failure. However, the molecular pathogenesis is not well understood. Here, we investigated 17 mutations associated with this disease, and our results showed that most disease-related mutations are partial loss-of-function mutations, with three mutations being particularly severe. Mutant MTU1 is rapidly degraded by mitochondrial caseinolytic peptidase (CLPP) through a direct interaction with its chaperone protein CLPX. Notably, knockdown of CLPP significantly increased mutant MTU1 protein expression and mt-tRNA 2-thiolation, suggesting that accelerated proteolysis of mutant MTU1 plays a role in disease pathogenesis. In addition, molecular dynamics simulations demonstrated that disease-associated mutations may lead to abnormal intermolecular interactions, thereby impairing MTU1 enzyme activity. Finally, clinical data analysis underscores a significant correlation between patient prognosis and residual 2-thiolation levels, which is partially consistent with the AlphaMissense predictions. These findings provide a comprehensive understanding of MTU1-related diseases, offering prospects for modification-based diagnostics and novel therapeutic strategies centered on targeting CLPP.
MeSH term(s)	Humans ; Endopeptidase Clp/genetics ; Endopeptidase Clp/metabolism ; Mitochondria/genetics ; Mitochondria/metabolism ; Mutation ; Peptide Hydrolases/genetics ; Proteolysis ; RNA, Mitochondrial/metabolism ; RNA, Transfer/metabolism ; tRNA Methyltransferases/genetics ; Mitochondrial Proteins/metabolism
Chemical Substances	Endopeptidase Clp (EC 3.4.21.92) ; Peptide Hydrolases (EC 3.4.-) ; RNA, Mitochondrial ; RNA, Transfer (9014-25-9) ; TRMU protein, human (EC 2.1.1.61) ; tRNA Methyltransferases (EC 2.1.1.-) ; Mitochondrial Proteins
Language	English
Publishing date	2023-12-19
Publishing country	England
Document type	Journal Article
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkad1197
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Zs.A 1067: Show issues

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Article ; Online: Export of RNA-derived modified nucleosides by equilibrative nucleoside transporters defines the magnitude of autophagy response and Zika virus replication.

Shi, Sheng-Lan / Fukuda, Hiroyuki / Chujo, Takeshi / Kouwaki, Takahisa / Oshiumi, Hiroyuki / Tomizawa, Kazuhito / Wei, Fan-Yan

RNA biology

2021 Volume 18, Issue sup1, Page(s) 478–495

Abstract	RNA contains a wide variety of posttranscriptional modifications covalently attached to its base or sugar group. These modified nucleosides are liberated from RNA molecules as the consequence of RNA catabolism and released into extracellular space, but the molecular mechanism of extracellular transport and its pathophysiological implications have been unclear. In the present study, we discovered that RNA-derived modified nucleosides are exported to extracellular space through equilibrative nucleoside transporters 1 and 2 (ENT1 and ENT2), with ENT1 showing higher preference for modified nucleosides than ENT2. Pharmacological inhibition or genetic deletion of ENT1 and ENT2 significantly attenuated export of modified nucleosides thereby resulting in their accumulation in cytosol. Using mutagenesis strategy, we identified an amino acid residue in ENT1 that is involved in the discrimination of unmodified and modified nucleosides. In ENTs-deficient cells, the elevated levels of intracellular modified nucleosides were closely associated with an induction of autophagy response as evidenced by increased LC3-II level. Importantly, we performed a screening of modified nucleosides capable of inducing autophagy and found that 1-methylguanosine (m
MeSH term(s)	Active Transport, Cell Nucleus ; Autophagy ; Equilibrative Nucleoside Transporter 1/genetics ; Equilibrative Nucleoside Transporter 1/metabolism ; Equilibrative-Nucleoside Transporter 2/genetics ; Equilibrative-Nucleoside Transporter 2/metabolism ; Humans ; Nucleosides/chemistry ; Nucleosides/genetics ; Nucleosides/metabolism ; RNA/genetics ; RNA/metabolism ; Tumor Cells, Cultured ; Virus Replication ; Zika Virus/physiology ; Zika Virus Infection/genetics ; Zika Virus Infection/pathology ; Zika Virus Infection/virology
Chemical Substances	Equilibrative Nucleoside Transporter 1 ; Equilibrative-Nucleoside Transporter 2 ; Nucleosides ; SLC29A1 protein, human ; SLC29A2 protein, human ; RNA (63231-63-0)
Language	English
Publishing date	2021-08-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2159587-2
ISSN	1555-8584 ; 1555-8584
ISSN (online)	1555-8584
ISSN	1555-8584
DOI	10.1080/15476286.2021.1960689
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Article ; Online: Cooperative methylation of human tRNA3Lys at positions A58 and U54 drives the early and late steps of HIV-1 replication.

Fukuda, Hiroyuki / Chujo, Takeshi / Wei, Fan-Yan / Shi, Sheng-Lan / Hirayama, Mayumi / Kaitsuka, Taku / Yamamoto, Takahiro / Oshiumi, Hiroyuki / Tomizawa, Kazuhito

Nucleic acids research

2021 Volume 49, Issue 20, Page(s) 11855–11867

Abstract: Retroviral infection requires reverse transcription, and the reverse transcriptase (RT) uses cellular tRNA as its primer. In humans, the TRMT6-TRMT61A methyltransferase complex incorporates N1-methyladenosine modification at tRNA position 58 (m1A58); ... ...

Abstract	Retroviral infection requires reverse transcription, and the reverse transcriptase (RT) uses cellular tRNA as its primer. In humans, the TRMT6-TRMT61A methyltransferase complex incorporates N1-methyladenosine modification at tRNA position 58 (m1A58); however, the role of m1A58 as an RT-stop site during retroviral infection has remained questionable. Here, we constructed TRMT6 mutant cells to determine the roles of m1A in HIV-1 infection. We confirmed that tRNA3Lys m1A58 was required for in vitro plus-strand strong-stop by RT. Accordingly, infectivity of VSV-G pseudotyped HIV-1 decreased when the virus contained m1A58-deficient tRNA3Lys instead of m1A58-modified tRNA3Lys. In TRMT6 mutant cells, the global protein synthesis rate was equivalent to that of wild-type cells. However, unexpectedly, plasmid-derived HIV-1 expression showed that TRMT6 mutant cells decreased accumulation of HIV-1 capsid, integrase, Tat, Gag, and GagPol proteins without reduction of HIV-1 RNAs in cells, and fewer viruses were produced. Moreover, the importance of 5,2'-O-dimethyluridine at U54 of tRNA3Lys as a second RT-stop site was supported by conservation of retroviral genome-tRNALys sequence-complementarity, and TRMT6 was required for efficient 5-methylation of U54. These findings illuminate the fundamental importance of tRNA m1A58 modification in both the early and late steps of HIV-1 replication, as well as in the cellular tRNA modification network.
MeSH term(s)	Animals ; HEK293 Cells ; HIV-1/physiology ; HeLa Cells ; Humans ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Methylation ; Mice ; Mutation ; RNA Processing, Post-Transcriptional ; RNA, Transfer, Lys/chemistry ; RNA, Transfer, Lys/metabolism ; Virus Replication
Chemical Substances	CRLS1 protein, human ; Membrane Proteins ; RNA, Transfer, Lys
Language	English
Publishing date	2021-10-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkab879
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