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Title

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

AuthorsRodríguez-Vargas, José Manuel; Majuelos-Melguizo, Jara; Peralta, Andreína; López-Rivas, Abelardo ; Oliver, Francisco Javier
KeywordsStarvation
Autophagy
DNA damage
PARP-1
mTOR
AMPK
Issue Date24-Apr-2012
PublisherNature Publishing Group
CitationCell Research 22(7): 1181-1198 (2012)
AbstractIn 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.
DescriptionRodríguez-Vargas, José Manuel et al.
Publisher version (URL)http://dx.doi.org/10.1038/cr.2012.70
URIhttp://hdl.handle.net/10261/122540
DOI10.1038/cr.2012.70
Identifierse-issn: 1748-7838
issn: 1001-0602
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