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

作　　者：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 

机构地区：[1]Instituto de Parasitologia y Biomedicina Lopez Neyra, CSIC, Avda. Conocimiento s/n, 18100 Armilla, Granada, Spain [2]IBIMER, Universidad de Granada, Granada, Spain [3]CIBERED, Hospital Universitario san Cecilio, Granada, Spain [4]Departamento de Ciencias Experimentales, Universidad de Jaen, Jaen, Spain [5]SCABIMER, CSIC, Sevilla, Spain [6]Danish Cancer Society Institute of Cancer Biology, Strandboulevarden 49, Copenhagen DK-2100, Denmark

出　　处：《Cell Research》2012年第7期1181-1198,共18页细胞研究（英文版）

摘　　要：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.

关 键 词：STARVATION AUTOPHAGY DNA damage PAP  P-1 mTOR AMPK 

分 类 号：Q523[生物学—生物化学] Q255