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

Author:

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

Abstract

AbstractAccumulation 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. UsingErcc1-defective mice andXpgknock-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.

Funder

Fondazione Umberto Veronesi

U.S. Department of Health & Human Services | NIH | National Institute of Environmental Health Sciences

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry

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