ROS-induced DNA damage and PARP-1 are required for optimal induction of starvation-induced autophagy
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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, María Isabel; Muñoz-Gámez, José Antonio; de Almodóvar, Mariano Ruiz; Siles, Eva; Rivas, Abelardo López; Jaattela, Marja; Oliver, F Javier.
I: Endocytobiosis and Cell Research, Bind 22, Nr. 7, 2012, s. 1181-98.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - ROS-induced DNA damage and PARP-1 are required for optimal induction of starvation-induced autophagy
AU - Rodríguez-Vargas, José Manuel
AU - Ruiz-Magaña, María José
AU - Ruiz-Ruiz, Carmen
AU - Majuelos-Melguizo, Jara
AU - Peralta-Leal, Andreína
AU - Rodríguez, María Isabel
AU - Muñoz-Gámez, José Antonio
AU - de Almodóvar, Mariano Ruiz
AU - Siles, Eva
AU - Rivas, Abelardo López
AU - Jaattela, Marja
AU - Oliver, F Javier
PY - 2012
Y1 - 2012
N2 - 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 ¿-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.
AB - 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 ¿-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.
U2 - 10.1038/cr.2012.70
DO - 10.1038/cr.2012.70
M3 - Journal article
C2 - 22525338
VL - 22
SP - 1181
EP - 1198
JO - Endocytobiosis and Cell Research
JF - Endocytobiosis and Cell Research
SN - 0256-1514
IS - 7
ER -
ID: 38488487