PARP-1 is involved in autophagy induced by DNA damage

Muñoz-Gámez, José Antonio; Rodríguez-Vargas, José Manuel; Quiles-Pérez, Rosa; Aguilar-Quesada, Rocío; Martín‐Oliva, David; Murcia, Gilbert de; Murcia, Josiane Ménissier de; Almendros, Antonio; Almodóvar, Mariano Ruiz de; Oliver, F. Javier

doi:10.4161/auto.5.1.7272

Cited by 215 publications

(154 citation statements)

References 39 publications

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“…Chemotherapyinduced autophagy may promote cell resistance against it. Doxorubicin-induced DNA damage stimulates cytoprotective autophagy through a PARP-1-dependent pathway [48]. Similarly, cisplatin-induced autophagy delays apoptosis in renal tubular epithelial cells [45] and tamoxifen and camptothecin-induced autophagy increases MCF7 breast carcinoma cell line viability [42,46].…”

Section: Discussionmentioning

confidence: 99%

BNIP3 protects HepG2 cells against etoposide-induced cell death under hypoxia by an autophagy-independent pathway

Cosse

Rommelaere

Ninane

et al. 2010

Biochemical Pharmacology

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Tumor hypoxia is a common characteristic of most solid tumors and is correlated with poor prognosis for patients partly because hypoxia promotes resistance to cancer therapy. Hypoxia selects cancer cells that are resistant to apoptosis and allows the onset of mechanisms that promote cancer cells survival including autophagy. Previously, we showed that human hepatoma HepG2 cells were protected under hypoxia against the etoposide-induced apoptosis.In this study, respective putative contribution of autophagy and BNIP3 in the protection conferred by hypoxia against the etoposide-induced apoptosis was investigated. We report that autophagy is induced by etoposide, a process that is not affected by hypoxic conditions. Using Atg5 siRNA, we show that etoposide-induced autophagy promotes apoptotic cell death under normoxia but not under hypoxia. Then, we investigated whether the hypoxia-induced protein BNIP3 could explain the different effect of autophagy on cell death under hypoxia or normoxia. We show that the silencing of BNIP3 does not affect autophagy whatever the pO 2 but participates in the protective effect of hypoxia against etoposide-induced apoptosis.Together, these results suggest that autophagy might be involved in etoposide-induced cell death only under normoxia and that BNIP3 is a major effector of the protective mechanism conferred by hypoxia to protect cancer cells against etoposide-induced apoptotic cell death.

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Section: Discussionmentioning

confidence: 99%

BNIP3 protects HepG2 cells against etoposide-induced cell death under hypoxia by an autophagy-independent pathway

Cosse

Rommelaere

Ninane

et al. 2010

Biochemical Pharmacology

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“…47 In fact, DNA repair requires ATP at several steps, including DNA unwinding by helicases during nucleotide-excision repair (NER), 51 ATP-dependent chromatin remodeling complexes in DSB repair 52 and PARP activity, which consumes NAD þ and can cause energy collapse in DNA-damaged cells. 53,54 However, direct evidence to corroborate this hypothesis is still lacking.…”

Section: The Role Of Autophagy In Dna Repairmentioning

confidence: 93%

“…As a consequence, AMPK is activated, thereby inhibiting mTOR and inducing autophagy. 53,54 It is worth noting that autophagy activation was shown to precede phosphorylation of ATM and p53 and activation of DNA repair proteins in response to capsaicin treatment, revealing an intricate pathway in which autophagy acts upstream, and not just as a consequence, of DDR activation. 82 BNIP3 is a Bcl-2 homologous protein and is activated after conditions of stress such as hypoxia.…”

Section: Pathways Connecting Ddr To Autophagymentioning

confidence: 99%

Autophagy and genomic integrity

et al. 2013

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DNA lesions, constantly produced by endogenous and exogenous sources, activate the DNA damage response (DDR), which involves detection, signaling and repair of the damage. Autophagy, a lysosome-dependent degradation pathway that is activated by stressful situations such as starvation and oxidative stress, regulates cell fate after DNA damage and also has a pivotal role in the maintenance of nuclear and mitochondrial genomic integrity. Here, we review important evidence regarding the role played by autophagy in preventing genomic instability and tumorigenesis, as well as in micronuclei degradation. Several pathways governing autophagy activation after DNA injury and the influence of autophagy upon the processing of genomic lesions are also discussed herein. In this line, the mechanisms by which several proteins participate in both DDR and autophagy, and the importance of this crosstalk in cancer and neurodegeneration will be presented in an integrated fashion. At last, we present a hypothetical model of the role played by autophagy in dictating cell fate after genotoxic stress.

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“…A recent study from our group has also implicated PARP-1 in autophagy induced by DNA damage and oxidative stress [6]. There are, however, important issues that remain unresolved, such as the involvement of PARP signaling in a physiologic model of autophagy as is the case for nutrient deprivation and the connection of PARP activation with the autophagic components.…”

Section: Introductionmentioning

confidence: 99%

“…Starvation induces ROS production, DNA damage and activation of PARP-1 PARP-1 is a nuclear enzyme activated by DNA damage; following genotoxic stress PARP-1 synthesizes a branched polymer of poly(ADP-ribose) or PAR that participates in the regulation of the nuclear homeostasis [3,6,8]. Many different cellular insults that cause DNA damage activate PARP-1 and induce PARP-1-dependent cell death.…”

Section: The Absence or Inhibition Of Parp-1 Delays Starvationinducedmentioning

confidence: 99%

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

et al. 2012

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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.

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PARP-1 is involved in autophagy induced by DNA damage

Cited by 215 publications

References 39 publications

BNIP3 protects HepG2 cells against etoposide-induced cell death under hypoxia by an autophagy-independent pathway

BNIP3 protects HepG2 cells against etoposide-induced cell death under hypoxia by an autophagy-independent pathway

Autophagy and genomic integrity

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

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