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

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.

ROS-Induced DNA Damage as an Underlying Cause of Aging

“…Depending on the structure and frequency of DNA damage, DNA repair processing can induce either mutagenesis that promotes cell survival and cancer or impede replication and transcription that promote cell death and aging. Interestingly, defects in transcriptional coupled(TC) repair observed in Ercc1 mutant mice display features of aging, which can be related to the accumulation of DNA damage resulting in stalled transcription complexes, particularly in long genes and in post-mitotic cells[23,24]. Another interesting example involves the induction of multiple telomere defects including telomere shortening, and in the long run, genetic instability, when G is specifically oxidized to 8oxoG in telomeres together with ablation of 8oxoG-specific DNA N-glycosylase OGG1[25].…”

A perspective on DNA damage-induced potentiation of the pentose phosphate shunt and reductive stress in chemoresistance

“…Here, we described a mechanism connecting transcription stalling caused by defective DNA repair with augmented intracellular ATP levels, which in turn allosterically inhibit the glycolytic enzyme ATP-dependent 6-phosphofructokinase (Pfk, best known as phosphofructokinase) to reroute glucose through the pentose phosphate pathway (PPP). Potentiation of the PPP is intrinsically associated with increased production of NADPH reducing equivalentswhich are generated in the oxidative branch of the pathwaythat in our experimental system is not paralleled by proportionate production of oxidant species and/or endogenous oxidoreductase activity, and therefore culminates in reductive stress 1 (Figure 1A).…”

Bacterial quorum sensing signal arrests phytoplankton cell division and protects against virus-induced mortality

“…Energy Production. In order to facilitate DNA synthesis and repair, the cell requires large ATP pools 52 , and there were several lines of evidence to support ATP generation in HHQ exposed cells. First, an increased relative transcript abundance of enzymes in the tricarboxylic acid (TCA) cycle (i.e., isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, succinate dehydrogenase, fumarase, and malate dehydrogenase) ( Fig.…”