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. Wit, Roel C. Janssens, René Leen, André B. P. Kuilenburg, Nico Mitro, Jan H. J. Hoeijmakers and Pier G. Mastroberardino ()
Additional contact information
Chiara Milanese: Erasmus University Medical Center
Cíntia R. Bombardieri: Erasmus University Medical Center
Sara Sepe: Erasmus University Medical Center
Sander Barnhoorn: Erasmus University Medical Center
César Payán-Goméz: Erasmus University Medical Center
Donatella Caruso: University of Milan
Matteo Audano: University of Milan
Silvia Pedretti: University of Milan
Wilbert P. Vermeij: Princess Máxima Center for Pediatric Oncology
Renata M. C. Brandt: Erasmus University Medical Center
Akos Gyenis: Erasmus University Medical Center
Mirjam M. Wamelink: VU University Medical Center
Annelieke S. Wit: Erasmus University Medical Center
Roel C. Janssens: Erasmus University Medical Center
René Leen: Academic Medical Center
André B. P. Kuilenburg: Academic Medical Center
Nico Mitro: University of Milan
Jan H. J. Hoeijmakers: Erasmus University Medical Center
Pier G. Mastroberardino: Erasmus University Medical Center

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: 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.

Date: 2019
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-019-12640-5 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12640-5

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-019-12640-5

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().