Ítem
Acceso Abierto
DNA damage and transcription stress cause ATP-mediated redesign of metabolism and potentiation of anti-oxidant buffering
Título de la revista
Autores
Milanese, Chiara
Bombardieri, Cíntia R.
Sepe, Sara
Barnhoorn, Sander
Payan-Gomez, Cesar
Caruso, Donatella
Audano, Matteo
Pedretti, Silvia
Vermeij, Wilbert P.
Brandt, Renata M. C.
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Fecha
2019
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Nature Publishing Group
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Resumen
Abstract
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).
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Keywords
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 , Ercc1 protein , 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 , Mice , Nadp , Nuclear proteins , Oxidation-reduction , Pentose phosphate pathway , Skin , Transcription factors , Transcription
