FIGURE 8:

Consequences of PARP1 activation critical for damaged cell survival. DNA damage complexity/dose-dependent PARP1 activation results in PARylation of target proteins and the decrease of NAD+ and ATP. PARylation at DNA damage sites dictates the recruitment of chromatin modifiers and DNA repair pathway choice and facilitates DNA repair. While PARylation also suppresses glycolysis through inhibition of HK, our results indicate that NAD+ consumption by PARylation also inhibits glycolysis. As a result, NAD+ consumption by PARP1 triggers an overall shift of metabolic reliance to oxphos. This contributes to the decrease of NADH. Importantly, in response to DNA damage and PARP1 activation, the oxphos pathway becomes critical for replenishment of ATP. Taken together, damage-induced PARP1 activation results in modulation of DNA repair and metabolic switch that together promote damaged cell survival.