TY - JOUR
T1 - DNA damage and transcription stress cause ATP-mediated redesign of metabolism and potentiation of anti-oxidant buffering
AU - Milanese, Chiara
AU - Bombardieri, Cíntia R.
AU - Sepe, Sara
AU - Barnhoorn, Sander
AU - Payán-Goméz, César
AU - Caruso, Donatella
AU - Audano, Matteo
AU - Pedretti, Silvia
AU - Vermeij, Wilbert P.
AU - Brandt, Renata M.C.
AU - Gyenis, Akos
AU - Wamelink, Mirjam M.
AU - de Wit, Annelieke S.
AU - Janssens, Roel C.
AU - Leen, René
AU - van Kuilenburg, André B.P.
AU - Mitro, Nico
AU - Hoeijmakers, Jan H.J.
AU - Mastroberardino, Pier G.
N1 - Funding Information:
P.G.M. is supported by a grant from the Netherlands Genomics Initiative (NGI/NWO 05040202), a Marie Curie grant (IRG 247918), and the CEREBRAD grant under the EU-FP7 framework (project number 295552). C.M. has been partially supported by the Erasmus Medical Center (Louis Jeantet Foundation award to JHJH) and by the Fon-dazione Veronesi. The Extracellular Flux Analyzer by Seahorse Bioscience was purchased thanks to a generous donation from the “Dorpmans-Wigmans Stichting” (P.G.M.). J.H.J. H. acknowledges financial support of the National Institute of Health (NIH)/National Institute of Ageing (NIA) (1PO1 AG-17242-02), NIEHS (1UO1 ES011044), the Royal Academy of Arts and Sciences of the Netherlands (academia professorship) and Dam2Age, a European Research Council Advanced Grant and Oncode. The research leading to these results has received funding from the European Community’s Seventh Framework Programme (FP7/2007–2013) under grant agreement No. HEALTH-F2-2010-259893.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-019-12640-5
DO - 10.1038/s41467-019-12640-5
M3 - Article
C2 - 31653834
AN - SCOPUS:85074162272
SN - 2041-1723
VL - 10
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4887
ER -
