ROS-induced DNA damage and PARP-1 are required for optimal induction of starvation-induced autophagy Rodríguez-Vargas, José Manuel Ruiz Magaña, María José Ruiz Ruiz, Carmen Majuelos-Melguizo, Jara Peralta-Leal, Andreína Rodríguez, M.I. Muñoz-Gámez, José Antonio Ruiz de Almodóvar, Mariano Siles, E. López-Rivas, Abelardo Jäättela, M. Oliver, Francisco Javier Starvation Autophagy DNA damage PARP-1 mTOR AMPK 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 γ-H2AX accumulation and comet assay, with PARP-1 knockout cells displaying a reduction in both parameters. During starvation, ROSinduced 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-induced autophagy. Thus, the PARP signaling pathway is a key regulator of the initial steps of autophagy commitment following starvation. 2024-01-03T11:39:24Z 2024-01-03T11:39:24Z 2012-07 journal article J.M. Rodríguez-Vargas, M.J. Ruiz-Magaña, C. Ruiz-Ruiz, J. Majuelos-Melguizo, A. Peralta-Leal, M.I. Rodríguez, J.A. Muñoz-Gámez, M. Ruiz de Almodóvar, E. Siles, A. López-Rivas, M. Jäättela y F.J. Oliver. ROS-induced DNA damage and PARP-1 are required for optimal induction of starvation-induced autophagy. Cell Res. 2012 Jul;22(7):1181-98 https://hdl.handle.net/10481/86546 10.1038/cr.2012.70 eng http://creativecommons.org/licenses/by-nc-nd/3.0/ open access Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License NATURE-SHANGAI INSTITUTES FOR BIOLOGICAL SCIENCES