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Research Paper

PARP-1 is involved in autophagy induced by DNA damage

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

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Autophagy is a lysosome-dependent degradative pathway frequently activated in tumor cells treated with chemotherapy or radiation. PARP-1 has been implicated in different pathways leading to cell death and its inhibition potentiates chemotherapy-induced cell death. Whether PARP-1 participates in the cell’s decision to commit to autophagy following DNA damage is still not known. To address this issue PARP-1 wild type and deficient cells have been treated with a dose of doxorubicin that induces autophagy.  Electron microscopy examination and GFP-LC3 transfection revealed autophagic vesicles and increased expression of genes involved in autophagy (bnip-3, cathepsin b and l and beclin-1) in wild type cells treated with doxo but not in parp-1^-/- cells or cells treated with a PARP inhibitor. Mechanistically the lack of autophagic features in PARP-1 deficient/PARP inhibited cells is attributed to prevention of ATP and NAD⁺ depletion and to the activation of the key autophagy regulator mTOR. Pharmacological or genetical inhibition of autophagy results in increased cell death, suggesting a protective role of autophagy induced by doxorubicin. These results suggest that autophagy might be cytoprotective during the response to DNA damage and suggest that PARP-1 activation is involved in the cell’s decision to undergo autophagy.

Authors

José Antonio Muñoz-Gámez

Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd) and Laboratory of Medical Research; Academical Hospital San Cecilio; Granada, Spain

José Manuel Rodríguez-Vargas

Instituto de Parasitología y Biomedicina López-Neyra; CSIC,Granada, Spain

Rosa Quiles-Pérez

Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd) and Laboratory of Medical Research; Academical Hospital San Cecilio; Granada, Spain

Rocío Aguilar-Quesada

Instituto de Parasitología y Biomedicina López-Neyra; CSIC,Granada, Spain

David Martín-Oliva

Departamento de Biología Celular; Universidad de Granada; Granada, Spain

Gilbert de Murcia

Departement Integrité du Genome; UMR 7100; CNRS; Strasbourg France

Josiane Menissier de Murcia

Departement Integrité du Genome; UMR 7100; CNRS; Strasbourg France

Antonio Almendros

Departamento de Biología Celular; Universidad de Granada; Granada, Spain

Mariano Ruiz de Almodóvar

IBIMER; Universidad de Grandada; Granada Spain

F. Javier Oliver

Instituto de Parasitología y Biomedicina López-Neyra; CSIC; Granada, Spain

This is an open-access article

 Download PDF

If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.