Figure 3.

Schematic representation of main pathways regulating the DDR-mediated autophagic response. ATM is activated in response to DNA damage by the MRN complex and initiates a pathway that results in activation of AMPK and its target TSC2 (TSC complex subunit 2), which removes the inhibitory effect of MTORC1 on autophagy, promoting ULK1-dependent autophagosome formation. ATM directly phosphorylates and stabilizes TP53, which activates the expression of several regulators of the autophagic pathway including SESNs (Sestrin family genes), DAPK (death-associated protein kinase 1) and PTEN (phosphatase and tensin homolog). ATM contributes to the activation of AATF (apoptosis antagonizing transcription factor) and leads to increased transcription of two mTOR inhibitors, DDIT4 (DNA damage inducible transcript 4) and DEPTOR (DEP domain containing MTOR interacting protein). DNA damage response activates MAPK8 (mitogen-activated protein kinase 8) and NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells) pathways, that induce expression of several autophagy related genes, including BECN1. PARP1 activation in response to DNA damage causes reduction in NAD+ (nicotinamide adenine dinucleotide) and ATP (adenosine triphosphate) pool depletion; elevated AMP (adenosine monophosphate) levels are sensed by AMPK, leading to its activation and induction of autophagy. Black arrows (↑) and perpendicular lines (⊥) indicate activation and repression, respectively. Blue arrows indicate transcriptional regulation.