title: ROS-induced DNA damage and PARP-1 are required for optimal induction of starvation-induced autophagy.
abstract: 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, 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-induced autophagy. Thus, the PARP signaling pathway is a key regulator of the initial steps of autophagy commitment following starvation.
authors.affiliation: Instituto de Parasitología y Biomedicina López Neyra, CSIC, Avda. Conocimiento s/n, 18100 Armilla, Granada, Spain.
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Rodríguez-Vargas
authors.forename: María José
authors.initials: MJ
authors.lastname: Ruiz-Magaña
authors.forename: Carmen
authors.initials: C
authors.lastname: Ruiz-Ruiz
authors.forename: Jara
authors.initials: J
authors.lastname: Majuelos-Melguizo
authors.forename: Andreína
authors.initials: A
authors.lastname: Peralta-Leal
authors.forename: María Isabel
authors.initials: MI
authors.lastname: Rodríguez
authors.forename: José Antonio
authors.initials: JA
authors.lastname: Muñoz-Gámez
authors.forename: Mariano Ruiz
authors.initials: MR
authors.lastname: de Almodóvar
authors.forename: Eva
authors.initials: E
authors.lastname: Siles
authors.forename: Abelardo López
authors.initials: AL
authors.lastname: Rivas
authors.forename: Marja
authors.initials: M
authors.lastname: Jäättela
authors.forename: F Javier
authors.initials: FJ
authors.lastname: Oliver
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D004249:DNA Damage / Q000235:genetics / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D051379:Mice; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases