期刊
NATURE COMMUNICATIONS
卷 10, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-12640-5
关键词
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资金
- Netherlands Genomics Initiative [NGI/NWO 05040202]
- Marie Curie grant [IRG 247918]
- CEREBRAD grant under the EU-FP7 framework [295552]
- Erasmus Medical Center (Louis Jeantet Foundation)
- Fondazione Veronesi
- National Institute of Health (NIH)/National Institute of Ageing (NIA) [1PO1 AG-17242-02]
- NIEHS [1UO1 ES011044]
- Royal Academy of Arts and Sciences of the Netherlands
- Dam2Age, a European Research Council Advanced Grant
- Oncode
- European Community's Seventh Framework Programme (FP7/2007-2013) [HEALTH-F2-2010-259893]
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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