ROS-induced DNA damage and PARP-1 are required for optimal induction of starvation-induced autophagy

• Published in: Cell research 2012-07, Vol.22 (7), p.1181-1198
• Main Author: Jose Manuel Rodriguez-Vargas Maria Jose Ruiz-Magana Carmen Ruiz-Ruiz Jara Majuelos-Melguizo Andreina Peralta-Lea Maria Isabel Rodriguez Jose Antonio Munoz-Gaimez Mariano Ruiz de Almodovar Eva Siles Abelardo Lopez Rivas Marja Jaattela F Javier Oliver
• Format: Article
• Language: English
• Subjects: 631/337/1427; 631/80/82/39; 631/80/86/2369; Adaptations; Animals; Apoptosis; Apoptosis - genetics; Apoptosis - physiology; ATP; Autophagy - genetics; Autophagy - physiology; Bioassays; Biomedical and Life Sciences; Blotting, Western; Cell Biology; Cell Line; Cell Survival - genetics; Cell Survival - physiology; Comet assay; Deoxyribonucleic acid; DNA; DNA damage; DNA Damage - genetics; DNA Damage - physiology; DNA损伤; Fluorescent Antibody Technique; Inactivation; Life Sciences; Liver; Mice; Microscopy, Fluorescence; Models, Biological; Neonates; Nutrients; Original; original-article; Phagocytosis; Physiology; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerases - genetics; Poly(ADP-ribose) Polymerases - metabolism; Reactive Oxygen Species - metabolism; ROS; Signal transduction; Starvation; Stress; TOR protein; 信号机制; 应激反应; 细胞凋亡; 自噬; 诱导; 饥饿
• ISSN: 1001-0602; 1748-7838
• DOI: 10.1038/cr.2012.70

In response to nutrient stress, cells start an autophagy program that can lead to adaptation or death. The mechanisms underlying the signaling from starvation to the initiation of autophagy are not fully understood. In the current study we show that the absence or inactivation of PARP-1 strongly delays starvation-induced autophagy. We have found that DNA damage is an early event of starvation-induced autophagy as measured by y-H2AX accumulation and comet assay, with PARP-1 knockout cells displaying a reduction in both parameters. During starvation, ROS- induced DNA damage activates PARP-1, leading to ATP depletion （an early event after nutrient deprivation）. The absence of PARP-1 blunted AMPK activation and prevented the complete loss of mTOR activity, leading to a delay in autophagy. PARP-1 depletion favors apoptosis in starved cells, suggesting a pro-survival role of autophagy and PARP-1 activation after nutrient deprivation. In vivo results show that neonates of PARP-1 mutant mice subjected to acute starvation, also display deficient liver autophagy, implying a physiological role for PARP-1 in starvation-in- duced autophagy. Thus, the PARP signaling pathway is a key regulator of the initial steps of autophagy commitment following starvation.