Figure 4.

Implication of autophagy in DNA damage repair. Endogenous (e.g., dysfunctional mitochondria, top right) or exogenous (e.g., radiations or genotoxic stimuli, bottom left) sources of ROS and RNS induce DNA damage, whose primary sensors are PARP1 and ATM. Once activated by DNA breaks, PARP1 catalyses poly-ADP ribosylation of itself, as well as of other nuclear proteins, thereby leading to a massive decrease of NAD⁺ and to a subsequent energetic stress (bottom left). Upon DNA damage, ATM can activate p53-mediated transcription of autophagic genes (bottom right). Alternatively, cytosolic pool of ATM could be directly activated by ROS through a still unidentified mechanism and it directly induces the activation of LKB1 (centre). The issue of whether cytosolic and nuclear pool of ATM are interconnected still waits to be demonstrated. Both PARP1 and ATM signalling pathways converge on AMPK, whose activation induces the autophagic machinery to remove the main source of DNA damage and contribute to its repair through a negative feedback loop (top)