DNA damage induces down-regulation of PEPCK and G6P gene expression through degradation of PGC-1alpha.

Hepatic gluconeogenesis plays a crucial role in glucose homeostasis. Although it is well established that various cellular processes are modulated by DNA damage, whether the DNA damage signaling pathway regulates gluconeogenesis has not yet been studied. In this study, we found that mRNA levels of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6P), key enzymes for gluconeogenesis, were dramatically decreased upon IR- and UV-irradiation. PEPCK and G6P promoter activities were also suppressed by IR- and UV-irradiation, suggesting that PEPCK and G6P gene transcription are down-regulated upon DNA damage. We also found that the protein level of PGC-1α, which is a critical transcription factor for PEPCK gene expression, is decreased upon UV-irradiation. The decreased PGC-1α protein level was abolished by MG132, a potent proteasome inhibitor, suggesting that PGC-1α is degraded through the ubiquitin-proteasome pathway upon UV-irradiation. These results reveal a novel link between glucose metabolism and the DNA damage signaling pathway and suggest a possible role for PEPCK and G6P in the DNA damage response.