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

Chiara Milanese, Cíntia R. Bombardieri, Sara Sepe, Sander Barnhoorn, César Payán-Goméz, Donatella Caruso, Matteo Audano, Silvia Pedretti, Wilbert P. Vermeij, Renata M.C. Brandt, Akos Gyenis, Mirjam M. Wamelink, Annelieke S. de Wit, Roel C. Janssens, René Leen, André B.P. van Kuilenburg, Nico Mitro, Jan H.J. Hoeijmakers, Pier G. Mastroberardino

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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.

Original languageEnglish (US)
Article number4887
JournalNature Communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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