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 - 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.
KW - Adenosine Triphosphate/metabolism
KW - Allosteric Regulation
KW - Animals
KW - Antioxidants/metabolism
KW - Cockayne Syndrome/metabolism
KW - DNA Damage/genetics
KW - DNA Repair/genetics
KW - DNA-Binding Proteins/genetics
KW - Endonucleases/genetics
KW - Fibroblasts/metabolism
KW - Genomic Instability
KW - Glycolysis/physiology
KW - Metabolomics
KW - Mice
KW - Mice, Knockout
KW - NADP/metabolism
KW - Nuclear Proteins/genetics
KW - Oxidation-Reduction
KW - Pentose Phosphate Pathway/physiology
KW - Skin/cytology
KW - Transcription Factors/genetics
KW - Transcription, Genetic/genetics
UR - https://www.mendeley.com/catalogue/508c5bbc-c84e-38d7-94af-7d8c5f3f19b1/
U2 - 10.1038/s41467-019-12640-5
DO - 10.1038/s41467-019-12640-5
M3 - Article
C2 - 31653834
SN - 2041-1723
VL - 10
SP - 4887
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 4887
ER -