DNA damage and transcription stress cause ATP-mediated redesign of metabolism and potentiation of anti-oxidant buffering

Accumulation of DNA lesions causing transcription stress is associated with natural and accelerated aging and culminates with profound metabolic alterations. Our understanding of the mechanisms governing metabolic redesign upon genomic instability, however, is highly rudimentary. Using Ercc1-defecti...

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Autores:
Tipo de recurso:
Fecha de publicación:
2019
Institución:
Universidad del Rosario
Repositorio:
Repositorio EdocUR - U. Rosario
Idioma:
eng
OAI Identifier:
oai:repository.urosario.edu.co:10336/22636
Acceso en línea:
https://doi.org/10.1038/s41467-019-12640-5
https://repository.urosario.edu.co/handle/10336/22636
Palabra clave:
1 phosphofructokinase
Antimycin a1
Carbonyl cyanide 4 (trifluoromethoxy)phenylhydrazone
Glucose 6 phosphate dehydrogenase
Glucose transporter
Glutathione
Oligomycin
Pentose phosphate
Reduced nicotinamide adenine dinucleotide phosphate
Rotenone
Sugar phosphate
Adenosine triphosphate
Antioxidant
Dna binding protein
Dna excision repair protein ercc-5
Endonuclease
Nicotinamide adenine dinucleotide phosphate
Nuclear protein
Transcription factor
Aging
Antioxidant
Bioenergetics
Buffering
Dna
Enzyme activity
Metabolism
Phosphate
Redox conditions
Stress analysis
Ampk signaling
Animal experiment
Animal model
Antioxidant activity
Article
Bioenergy
Bioinformatics
Cell isolation
Cockayne syndrome
Cycloaddition
Dna damage
Dna repair
Dna transcription
Down regulation
Drug potentiation
Enzyme activity
Enzyme metabolism
Excision repair
Female
Flow cytometry
Gene expression level
Gene mutation
Genomic instability
Glycolysis
High performance liquid chromatography
Male
Metabolic activity assay
Metabolic flux analysis
Mitochondrial respiration
Mouse
Nonhuman
Nuclear reprogramming
Oxygen consumption
Pentose phosphate cycle
Peritoneum
Polymerase chain reaction
Protein phosphorylation
Redox stress
Rna isolation
Rna synthesis
Signal transduction
Skin biopsy
Skin fibroblast
Transcription coupled dna repair
Upregulation
Allosterism
Animal
Cytology
Dna damage
Fibroblast
Genetic transcription
Genetics
Knockout mouse
Metabolism
Metabolomics
Oxidation reduction reaction
Physiology
Skin
Animalia
Mus
Adenosine triphosphate
Allosteric regulation
Animals
Antioxidants
Cockayne syndrome
Dna damage
Dna repair
Dna-binding proteins
Endonucleases
Fibroblasts
Genomic instability
Glycolysis
Metabolomics
Mice
Nadp
Nuclear proteins
Oxidation-reduction
Pentose phosphate pathway
Skin
Transcription factors
knockout
mouse
genetic
Ercc1 protein
Mice
Transcription
Rights
License
Abierto (Texto Completo)
id EDOCUR2_b4067b78cfb9e0c1c6a8aa60c4de6bfc
oai_identifier_str oai:repository.urosario.edu.co:10336/22636
network_acronym_str EDOCUR2
network_name_str Repositorio EdocUR - U. Rosario
repository_id_str
dc.title.spa.fl_str_mv DNA damage and transcription stress cause ATP-mediated redesign of metabolism and potentiation of anti-oxidant buffering
title DNA damage and transcription stress cause ATP-mediated redesign of metabolism and potentiation of anti-oxidant buffering
spellingShingle DNA damage and transcription stress cause ATP-mediated redesign of metabolism and potentiation of anti-oxidant buffering
1 phosphofructokinase
Antimycin a1
Carbonyl cyanide 4 (trifluoromethoxy)phenylhydrazone
Glucose 6 phosphate dehydrogenase
Glucose transporter
Glutathione
Oligomycin
Pentose phosphate
Reduced nicotinamide adenine dinucleotide phosphate
Rotenone
Sugar phosphate
Adenosine triphosphate
Antioxidant
Dna binding protein
Dna excision repair protein ercc-5
Endonuclease
Nicotinamide adenine dinucleotide phosphate
Nuclear protein
Transcription factor
Aging
Antioxidant
Bioenergetics
Buffering
Dna
Enzyme activity
Metabolism
Phosphate
Redox conditions
Stress analysis
Ampk signaling
Animal experiment
Animal model
Antioxidant activity
Article
Bioenergy
Bioinformatics
Cell isolation
Cockayne syndrome
Cycloaddition
Dna damage
Dna repair
Dna transcription
Down regulation
Drug potentiation
Enzyme activity
Enzyme metabolism
Excision repair
Female
Flow cytometry
Gene expression level
Gene mutation
Genomic instability
Glycolysis
High performance liquid chromatography
Male
Metabolic activity assay
Metabolic flux analysis
Mitochondrial respiration
Mouse
Nonhuman
Nuclear reprogramming
Oxygen consumption
Pentose phosphate cycle
Peritoneum
Polymerase chain reaction
Protein phosphorylation
Redox stress
Rna isolation
Rna synthesis
Signal transduction
Skin biopsy
Skin fibroblast
Transcription coupled dna repair
Upregulation
Allosterism
Animal
Cytology
Dna damage
Fibroblast
Genetic transcription
Genetics
Knockout mouse
Metabolism
Metabolomics
Oxidation reduction reaction
Physiology
Skin
Animalia
Mus
Adenosine triphosphate
Allosteric regulation
Animals
Antioxidants
Cockayne syndrome
Dna damage
Dna repair
Dna-binding proteins
Endonucleases
Fibroblasts
Genomic instability
Glycolysis
Metabolomics
Mice
Nadp
Nuclear proteins
Oxidation-reduction
Pentose phosphate pathway
Skin
Transcription factors
knockout
mouse
genetic
Ercc1 protein
Mice
Transcription
title_short DNA damage and transcription stress cause ATP-mediated redesign of metabolism and potentiation of anti-oxidant buffering
title_full DNA damage and transcription stress cause ATP-mediated redesign of metabolism and potentiation of anti-oxidant buffering
title_fullStr DNA damage and transcription stress cause ATP-mediated redesign of metabolism and potentiation of anti-oxidant buffering
title_full_unstemmed DNA damage and transcription stress cause ATP-mediated redesign of metabolism and potentiation of anti-oxidant buffering
title_sort DNA damage and transcription stress cause ATP-mediated redesign of metabolism and potentiation of anti-oxidant buffering
dc.subject.keyword.spa.fl_str_mv 1 phosphofructokinase
Antimycin a1
Carbonyl cyanide 4 (trifluoromethoxy)phenylhydrazone
Glucose 6 phosphate dehydrogenase
Glucose transporter
Glutathione
Oligomycin
Pentose phosphate
Reduced nicotinamide adenine dinucleotide phosphate
Rotenone
Sugar phosphate
Adenosine triphosphate
Antioxidant
Dna binding protein
Dna excision repair protein ercc-5
Endonuclease
Nicotinamide adenine dinucleotide phosphate
Nuclear protein
Transcription factor
Aging
Antioxidant
Bioenergetics
Buffering
Dna
Enzyme activity
Metabolism
Phosphate
Redox conditions
Stress analysis
Ampk signaling
Animal experiment
Animal model
Antioxidant activity
Article
Bioenergy
Bioinformatics
Cell isolation
Cockayne syndrome
Cycloaddition
Dna damage
Dna repair
Dna transcription
Down regulation
Drug potentiation
Enzyme activity
Enzyme metabolism
Excision repair
Female
Flow cytometry
Gene expression level
Gene mutation
Genomic instability
Glycolysis
High performance liquid chromatography
Male
Metabolic activity assay
Metabolic flux analysis
Mitochondrial respiration
Mouse
Nonhuman
Nuclear reprogramming
Oxygen consumption
Pentose phosphate cycle
Peritoneum
Polymerase chain reaction
Protein phosphorylation
Redox stress
Rna isolation
Rna synthesis
Signal transduction
Skin biopsy
Skin fibroblast
Transcription coupled dna repair
Upregulation
Allosterism
Animal
Cytology
Dna damage
Fibroblast
Genetic transcription
Genetics
Knockout mouse
Metabolism
Metabolomics
Oxidation reduction reaction
Physiology
Skin
Animalia
Mus
Adenosine triphosphate
Allosteric regulation
Animals
Antioxidants
Cockayne syndrome
Dna damage
Dna repair
Dna-binding proteins
Endonucleases
Fibroblasts
Genomic instability
Glycolysis
Metabolomics
Mice
Nadp
Nuclear proteins
Oxidation-reduction
Pentose phosphate pathway
Skin
Transcription factors
topic 1 phosphofructokinase
Antimycin a1
Carbonyl cyanide 4 (trifluoromethoxy)phenylhydrazone
Glucose 6 phosphate dehydrogenase
Glucose transporter
Glutathione
Oligomycin
Pentose phosphate
Reduced nicotinamide adenine dinucleotide phosphate
Rotenone
Sugar phosphate
Adenosine triphosphate
Antioxidant
Dna binding protein
Dna excision repair protein ercc-5
Endonuclease
Nicotinamide adenine dinucleotide phosphate
Nuclear protein
Transcription factor
Aging
Antioxidant
Bioenergetics
Buffering
Dna
Enzyme activity
Metabolism
Phosphate
Redox conditions
Stress analysis
Ampk signaling
Animal experiment
Animal model
Antioxidant activity
Article
Bioenergy
Bioinformatics
Cell isolation
Cockayne syndrome
Cycloaddition
Dna damage
Dna repair
Dna transcription
Down regulation
Drug potentiation
Enzyme activity
Enzyme metabolism
Excision repair
Female
Flow cytometry
Gene expression level
Gene mutation
Genomic instability
Glycolysis
High performance liquid chromatography
Male
Metabolic activity assay
Metabolic flux analysis
Mitochondrial respiration
Mouse
Nonhuman
Nuclear reprogramming
Oxygen consumption
Pentose phosphate cycle
Peritoneum
Polymerase chain reaction
Protein phosphorylation
Redox stress
Rna isolation
Rna synthesis
Signal transduction
Skin biopsy
Skin fibroblast
Transcription coupled dna repair
Upregulation
Allosterism
Animal
Cytology
Dna damage
Fibroblast
Genetic transcription
Genetics
Knockout mouse
Metabolism
Metabolomics
Oxidation reduction reaction
Physiology
Skin
Animalia
Mus
Adenosine triphosphate
Allosteric regulation
Animals
Antioxidants
Cockayne syndrome
Dna damage
Dna repair
Dna-binding proteins
Endonucleases
Fibroblasts
Genomic instability
Glycolysis
Metabolomics
Mice
Nadp
Nuclear proteins
Oxidation-reduction
Pentose phosphate pathway
Skin
Transcription factors
knockout
mouse
genetic
Ercc1 protein
Mice
Transcription
dc.subject.keyword.eng.fl_str_mv knockout
mouse
genetic
Ercc1 protein
Mice
Transcription
description Accumulation of DNA lesions causing transcription stress is associated with natural and accelerated aging and culminates with profound metabolic alterations. Our understanding of the mechanisms governing metabolic redesign upon genomic instability, however, is highly rudimentary. Using Ercc1-defective mice and Xpg knock-out mice, we demonstrate that combined defects in transcription-coupled DNA repair (TCR) and in nucleotide excision repair (NER) directly affect bioenergetics due to declined transcription, leading to increased ATP levels. This in turn inhibits glycolysis allosterically and favors glucose rerouting through the pentose phosphate shunt, eventually enhancing production of NADPH-reducing equivalents. In NER/TCR-defective mutants, augmented NADPH is not counterbalanced by increased production of pro-oxidants and thus pentose phosphate potentiation culminates in an over-reduced redox state. Skin fibroblasts from the TCR disease Cockayne syndrome confirm results in animal models. Overall, these findings unravel a mechanism connecting DNA damage and transcriptional stress to metabolic redesign and protective antioxidant defenses. © 2019, The Author(s).
publishDate 2019
dc.date.created.spa.fl_str_mv 2019
dc.date.accessioned.none.fl_str_mv 2020-05-25T23:57:15Z
dc.date.available.none.fl_str_mv 2020-05-25T23:57:15Z
dc.type.eng.fl_str_mv article
dc.type.coarversion.fl_str_mv http://purl.org/coar/version/c_970fb48d4fbd8a85
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dc.type.spa.spa.fl_str_mv Artículo
dc.identifier.doi.none.fl_str_mv https://doi.org/10.1038/s41467-019-12640-5
dc.identifier.issn.none.fl_str_mv 20411723
dc.identifier.uri.none.fl_str_mv https://repository.urosario.edu.co/handle/10336/22636
url https://doi.org/10.1038/s41467-019-12640-5
https://repository.urosario.edu.co/handle/10336/22636
identifier_str_mv 20411723
dc.language.iso.spa.fl_str_mv eng
language eng
dc.relation.citationIssue.none.fl_str_mv No. 1
dc.relation.citationTitle.none.fl_str_mv Nature Communications
dc.relation.citationVolume.none.fl_str_mv Vol. 10
dc.relation.ispartof.spa.fl_str_mv Nature Communications, ISSN:20411723, Vol.10, No.1 (2019)
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dc.publisher.spa.fl_str_mv Nature Publishing Group
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spelling feb567b4-24f5-4f34-bcfc-f77b55a86345-1a1e3ab7b-916d-47ab-bff4-200631c43fdb-17f6bc8c5-2bb6-4298-8989-0cc5bceaa45d-18f176f9f-7e4d-46e4-8ace-e21129276137-1fe1aaba9-c808-4395-80be-f9ca6d292f96-1c86d0127-39d5-4490-b19e-a2bb27630849-1b4bca836-a627-4d2d-9e53-03aac3bcc623-1d4dce881-5144-462e-9a45-654fb3295bcb-1be6aa57e-ec05-45f4-a4d1-cfd9afbe0bc7-185c61937-a38b-4efb-a930-e829d50c0510-1be52aa3c-3396-423f-bde8-1eb50fe1a6ab-1774599a3-dc72-4a2a-8d3f-fde7b8c3c322-1145ba046-cf16-4008-aa32-00e890103c8d-1420d4109-ff25-490b-af89-aa9e542d3396-1b2155f02-3f96-46dc-b29f-de1c2f61d23a-1067f6dd1-a2e7-41b1-a4dc-f6bbabdf0753-122d7b8d2-0adb-4ad5-b752-5563bbd8b8b8-13d6f06c3-dd73-47c8-9d55-e4ad8447d738-1763272336002020-05-25T23:57:15Z2020-05-25T23:57:15Z2019Accumulation of DNA lesions causing transcription stress is associated with natural and accelerated aging and culminates with profound metabolic alterations. Our understanding of the mechanisms governing metabolic redesign upon genomic instability, however, is highly rudimentary. Using Ercc1-defective mice and Xpg knock-out mice, we demonstrate that combined defects in transcription-coupled DNA repair (TCR) and in nucleotide excision repair (NER) directly affect bioenergetics due to declined transcription, leading to increased ATP levels. This in turn inhibits glycolysis allosterically and favors glucose rerouting through the pentose phosphate shunt, eventually enhancing production of NADPH-reducing equivalents. In NER/TCR-defective mutants, augmented NADPH is not counterbalanced by increased production of pro-oxidants and thus pentose phosphate potentiation culminates in an over-reduced redox state. Skin fibroblasts from the TCR disease Cockayne syndrome confirm results in animal models. Overall, these findings unravel a mechanism connecting DNA damage and transcriptional stress to metabolic redesign and protective antioxidant defenses. © 2019, The Author(s).application/pdfhttps://doi.org/10.1038/s41467-019-12640-520411723https://repository.urosario.edu.co/handle/10336/22636engNature Publishing GroupNo. 1Nature CommunicationsVol. 10Nature Communications, ISSN:20411723, Vol.10, No.1 (2019)https://www.scopus.com/inward/record.uri?eid=2-s2.0-85074162272&doi=10.1038%2fs41467-019-12640-5&partnerID=40&md5=7c7a724f4d871305d5f6cbed2d0b4284Abierto (Texto Completo)http://purl.org/coar/access_right/c_abf2instname:Universidad del Rosarioreponame:Repositorio Institucional EdocUR1 phosphofructokinaseAntimycin a1Carbonyl cyanide 4 (trifluoromethoxy)phenylhydrazoneGlucose 6 phosphate dehydrogenaseGlucose transporterGlutathioneOligomycinPentose phosphateReduced nicotinamide adenine dinucleotide phosphateRotenoneSugar phosphateAdenosine triphosphateAntioxidantDna binding proteinDna excision repair protein ercc-5EndonucleaseNicotinamide adenine dinucleotide phosphateNuclear proteinTranscription factorAgingAntioxidantBioenergeticsBufferingDnaEnzyme activityMetabolismPhosphateRedox conditionsStress analysisAmpk signalingAnimal experimentAnimal modelAntioxidant activityArticleBioenergyBioinformaticsCell isolationCockayne syndromeCycloadditionDna damageDna repairDna transcriptionDown regulationDrug potentiationEnzyme activityEnzyme metabolismExcision repairFemaleFlow cytometryGene expression levelGene mutationGenomic instabilityGlycolysisHigh performance liquid chromatographyMaleMetabolic activity assayMetabolic flux analysisMitochondrial respirationMouseNonhumanNuclear reprogrammingOxygen consumptionPentose phosphate cyclePeritoneumPolymerase chain reactionProtein phosphorylationRedox stressRna isolationRna synthesisSignal transductionSkin biopsySkin fibroblastTranscription coupled dna repairUpregulationAllosterismAnimalCytologyDna damageFibroblastGenetic transcriptionGeneticsKnockout mouseMetabolismMetabolomicsOxidation reduction reactionPhysiologySkinAnimaliaMusAdenosine triphosphateAllosteric regulationAnimalsAntioxidantsCockayne syndromeDna damageDna repairDna-binding proteinsEndonucleasesFibroblastsGenomic instabilityGlycolysisMetabolomicsMiceNadpNuclear proteinsOxidation-reductionPentose phosphate pathwaySkinTranscription factorsknockoutmousegeneticErcc1 proteinMiceTranscriptionDNA damage and transcription stress cause ATP-mediated redesign of metabolism and potentiation of anti-oxidant bufferingarticleArtículohttp://purl.org/coar/version/c_970fb48d4fbd8a85http://purl.org/coar/resource_type/c_6501Milanese, ChiaraBombardieri, Cíntia R.Sepe, SaraBarnhoorn, SanderCaruso, DonatellaAudano, MatteoPedretti, SilviaVermeij, Wilbert P.Brandt, Renata M. C.Gyenis, AkosWamelink, Mirjam M.de Wit, Annelieke S.Janssens, Roel C.Leen, Renévan Kuilenburg, André B. P.Mitro, NicoHoeijmakers, Jan H. J.Mastroberardino, Pier G.Payan-Gomez, CesarORIGINALs41467-019-12640-5.pdfapplication/pdf2921302https://repository.urosario.edu.co/bitstreams/b039efc5-5db6-4d77-9fb8-36ac51b79db3/downloade99c83ad4ad385973c06314ecb680f01MD51TEXTs41467-019-12640-5.pdf.txts41467-019-12640-5.pdf.txtExtracted texttext/plain103749https://repository.urosario.edu.co/bitstreams/ab1b431a-6826-4259-86c9-102e8daf753b/download57502ee53b04f959eea25f213c2797a4MD52THUMBNAILs41467-019-12640-5.pdf.jpgs41467-019-12640-5.pdf.jpgGenerated Thumbnailimage/jpeg3889https://repository.urosario.edu.co/bitstreams/b437f694-e7a2-483c-952d-9e0d9b6e1bd3/downloadc2a742f3bd4c70fdb529064891a3cd32MD5310336/22636oai:repository.urosario.edu.co:10336/226362022-05-02 07:37:20.532834https://repository.urosario.edu.coRepositorio institucional EdocURedocur@urosario.edu.co