Loss of Human TGS1 Hypermethylase Promotes Increased Telomerase RNA and Telomere Elongation.

Biocatalysis Coiled Bodies / metabolism Guanosine / metabolism HEK293 Cells HeLa Cells Humans Methylation Methyltransferases / deficiency Models, Biological Mutation / genetics Polyadenylation RNA / metabolism RNA Caps / metabolism Subcellular Fractions / metabolism Telomerase / metabolism Telomere / metabolism
TERT TGS1 cap hypermethylation hTR telomerase telomere elongation telomeres

Journal

Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691

Informations de publication

Date de publication:
04 02 2020
Historique:
received: 28 06 2019
revised: 09 11 2019
accepted: 31 12 2019
entrez: 6 2 2020
pubmed: 6 2 2020
medline: 17 3 2021
Statut: ppublish

Résumé

Biogenesis of the human telomerase RNA (hTR) involves a complex series of posttranscriptional modifications, including hypermethylation of the 5' mono-methylguanosine cap to a tri-methylguanosine cap (TMG). How the TMG cap affects hTR maturation is unknown. Here, we show that depletion of trimethylguanosine synthase 1 (TGS1), the enzyme responsible for cap hypermethylation, increases levels of hTR and telomerase. Diminished trimethylation increases hTR association with the cap-binding complex (CBC) and with Sm chaperone proteins. Loss of TGS1 causes an increase in accumulation of mature hTR in both the nucleus and the cytoplasm compared with controls. In TGS1 mutant cells, increased hTR assembles with telomerase reverse transcriptase (TERT) protein to yield elevated active telomerase complexes and increased telomerase activity, resulting in telomere elongation in cultured human cells. Our results show that TGS1-mediated hypermethylation of the hTR cap inhibits hTR accumulation, restrains levels of assembled telomerase, and limits telomere elongation.

Identifiants

DOI: 10.1016/j.celrep.2020.01.004 PMID: 32023455 PMC: PMC7156301
pubmed: 32023455
pii: S2211-1247(20)30013-9
doi: 10.1016/j.celrep.2020.01.004
pmc: PMC7156301
mid: NIHMS1568953
pii:
doi:

Substances chimiques

RNA Caps 0
telomerase RNA 0
Guanosine 12133JR80S
RNA 63231-63-0
Methyltransferases EC 2.1.1.-
trimethylguanosine synthase EC 2.1.1.-
Telomerase EC 2.7.7.49

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

1358-1372.e5

Subventions

Organisme : NIA NIH HHS
ID : R01 AG056575
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA197563
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007365
Pays : United States

Informations de copyright

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Interests The authors declare no competing interests.

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Auteurs

Lu Chen (L)

Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA.

Caitlin M Roake (CM)

Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA.

Alessandra Galati (A)

Dipartimento di Biologia e Biotecnologie, Sapienza Università di Roma, Roma, Italy.

Francesca Bavasso (F)

Dipartimento di Biologia e Biotecnologie, Sapienza Università di Roma, Roma, Italy.

Emanuela Micheli (E)

Dipartimento di Biologia e Biotecnologie, Sapienza Università di Roma, Roma, Italy.

Isabella Saggio (I)

Dipartimento di Biologia e Biotecnologie, Sapienza Università di Roma, Roma, Italy.

Stefan Schoeftner (S)

Cancer Epigenetic Group, Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie, Trieste, Italy.

Stefano Cacchione (S)

Dipartimento di Biologia e Biotecnologie, Sapienza Università di Roma, Roma, Italy.

Maurizio Gatti (M)

Dipartimento di Biologia e Biotecnologie, Sapienza Università di Roma, Roma, Italy; Istituto di Biologia e Patologia Molecolari (IBPM) del CNR, Roma, Italy.

Steven E Artandi (SE)

Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: sartandi@stanford.edu.

Grazia D Raffa (GD)

Dipartimento di Biologia e Biotecnologie, Sapienza Università di Roma, Roma, Italy. Electronic address: graziadaniela.raffa@uniroma1.it.

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Classifications MeSH

questionsmedicales.fr › Métabolisme › Biocatalyse › Loss of Human TGS1 Hypermethylase Promotes...
questionsmedicales.fr › Cellules › Structures cellulaires › Espace intracellulaire › Structures nucléaires › Espace intranucléaire › Corps nucléaires › Corps de Cajal › Loss of Human TGS1 Hypermethylase Promotes...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Nucléosides › Ribonucléosides › Guanosine › Loss of Human TGS1 Hypermethylase Promotes...
questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules HEK293 › Loss of Human TGS1 Hypermethylase Promotes...
questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules HeLa › Loss of Human TGS1 Hypermethylase Promotes...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Loss of Human TGS1 Hypermethylase Promotes...
questionsmedicales.fr › Métabolisme › Alkylation › Méthylation › Loss of Human TGS1 Hypermethylase Promotes...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Transferases › One-carbon group transferases › Methyltransferases › Loss of Human TGS1 Hypermethylase Promotes...
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles biologiques › Loss of Human TGS1 Hypermethylase Promotes...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Loss of Human TGS1 Hypermethylase Promotes...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Maturation post-transcriptionnelle des ARN › Maturation de l'extrémité 3' des ARN › Polyadénylation › Loss of Human TGS1 Hypermethylase Promotes...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › ARN › Loss of Human TGS1 Hypermethylase Promotes...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Nucléotides › Ribonucléotides › Nucléotides guanyliques › Coiffes des ARN › Loss of Human TGS1 Hypermethylase Promotes...
questionsmedicales.fr › Cellules › Structures cellulaires › Fractions subcellulaires › Loss of Human TGS1 Hypermethylase Promotes...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Nucléoprotéines › Protéines de liaison à l'ARN › Ribonucléoprotéines › Telomerase › Loss of Human TGS1 Hypermethylase Promotes...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Structures de chromosome › Télomère › Loss of Human TGS1 Hypermethylase Promotes...