PARP-1 is involved in autophagy induced by DNA damage

Autophagy. 2009 Jan;5(1):61-74. doi: 10.4161/auto.5.1.7272. Epub 2009 Jan 27.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Naphthylamine / analogs & derivatives
  • 1-Naphthylamine / pharmacology
  • 3T3 Cells
  • Adenosine Triphosphate / deficiency
  • Animals
  • Apoptosis / drug effects
  • Apoptosis Regulatory Proteins
  • Autophagy* / drug effects
  • Autophagy* / genetics
  • Autophagy-Related Protein 5
  • Beclin-1
  • Cell Survival / drug effects
  • DNA Damage*
  • Doxorubicin / pharmacology
  • Enzyme Activation / drug effects
  • Gene Deletion
  • Mice
  • Microtubule-Associated Proteins / metabolism
  • Mitochondria / drug effects
  • Mitochondria / enzymology
  • Mitochondria / ultrastructure
  • Models, Biological
  • NAD / deficiency
  • Naphthalimides / pharmacology
  • Necrosis / enzymology
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Poly(ADP-ribose) Polymerases / metabolism*
  • Protein Kinases / metabolism
  • Proteins / metabolism
  • Quinolones / pharmacology
  • Subcellular Fractions / drug effects
  • Subcellular Fractions / metabolism
  • TOR Serine-Threonine Kinases
  • Up-Regulation / drug effects

Substances

  • Apoptosis Regulatory Proteins
  • Atg5 protein, mouse
  • Autophagy-Related Protein 5
  • Beclin-1
  • Becn1 protein, mouse
  • Map1lc3b protein, mouse
  • Microtubule-Associated Proteins
  • Naphthalimides
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Proteins
  • Quinolones
  • NAD
  • 4-amino-1,8-naphthalimide
  • Doxorubicin
  • Adenosine Triphosphate
  • 1-Naphthylamine
  • Poly(ADP-ribose) Polymerases
  • Protein Kinases
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse