PARP-1 is involved in autophagy induced by DNA damage.
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.
Muñoz-Gámez
José Antonio
JA
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd) and Laboratory of Medical Research, Academical Hospital San Cecilio, Granada, Spain.
Rodríguez-Vargas
José Manuel
JM
Quiles-Pérez
Rosa
R
Aguilar-Quesada
Rocío
R
Martín-Oliva
David
D
de Murcia
Gilbert
G
Menissier de Murcia
Josiane
J
Almendros
Antonio
A
Ruiz de Almodóvar
Mariano
M
Oliver
F Javier
FJ
D015057:1-Naphthylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D016475:3T3 Cells; D000255:Adenosine Triphosphate / Q000172:deficiency; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004317:Doxorubicin / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D017353:Gene Deletion; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure; D008954:Models, Biological; D009243:NAD / Q000172:deficiency; D053644:Naphthalimides / Q000494:pharmacology; D009336:Necrosis / Q000201:enzymology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D015363:Quinolones / Q000494:pharmacology; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D015854:Up-Regulation / Q000187:drug effects
D051017:Apoptosis Regulatory Proteins; C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; C115010:Becn1 protein, mouse; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D053644:Naphthalimides; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011506:Proteins; D015363:Quinolones; D009243:NAD; C086538:4-amino-1,8-naphthalimide; D004317:Doxorubicin; D000255:Adenosine Triphosphate; D015057:1-Naphthylamine; D011065:Poly(ADP-ribose) Polymerases; D011494:Protein Kinases; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases