Fig. 7.

Primary fibroblasts derived from skin biopsy from a patient suffering profound GG-NER/TCR defects due to a gene XPG mutation show metabolic modifications. a PFK activity is reduced in the patient’s cell and b, c is paralleled by decreased glycolysis, measured as ECAR in extracellular flux analysis. Line graph in B represents real time glycolysis changes in basal condition and upon stimulation with glucose and oligomycin. n ≥ 3, data were obtained from two independent experiments. d In the patient’s cells, the thiol-disulfide redox equilibrium, which was measured after derivatization of oxidized and reduced cysteines with maleimides conjugated with different fluorophores, is shifted toward a reducing state. n ≥ 150, data were obtained from three independent experiments. e G6PD activity shows a consistent trend, which however did not reach statistical significance. n = 3, data were obtained from two independent experiments. f Schematic representing the model we propose. Accumulation of transcription-blocking lesions triggers an acute antioxidant response driven by metabolic redesign. In normal conditions, pro-oxidant species are the principal source of DNA damage. However, in GG-NER/TCR-deficient mice DNA damage accumulation is not caused by increased oxidative stress, but is rather due to compromised repair. Thus, the intrinsic antioxidant response in this case is not paralleled by increased reactive species and it culminates in an overall reduced redox state. Error bars indicate mean ± s.e.m. *p < 0.05, **p < 0.01, ***p < 0.001, Student’s t-test. Original data are provided as Source Data file