The human apurinic/apyrimidinic endonuclease-1 suppresses activation of poly(adp-ribose) polymerase-1 induced by DNA single strand breaks.
DNA single-strand breaks (SSB) activate poly (ADP-ribose) polymerase 1 (PARP1), which then polymerizes ADP-ribosyl groups on various nuclear proteins, consuming cellular energy. Although PARP1 has a role in repairing SSB, activation of PARP1 also causes necrosis and inflammation due to depletion of cellular energy. Here we show that the major mammalian apurinic/apyrimidinic (AP) endonuclease-1 (APE1), an essential DNA repair protein, binds to SSB and suppresses the activation of PARP1. APE1's high affinity for SSB requires Arg177, which is unique in mammalian APEs. PARP1's binding to the cleaved DNA was inhibited, and PARP1 activation was suppressed by the wild-type APE1, but not by the R177A mutant APE1 protein. Cells transiently transfected with the wild-type APE1 decreased the PARP1 activation after H2O2 treatment, while such suppression did not occur with the expression of the R177A APE1 mutant. These results suggest that APE1 suppresses the activation of PARP1 during the repair process of the DNA damage generated by oxidative stress, which may have an important implication for cells to avoid necrosis due to energy depletion.
Peddi
Srinivasa R
SR
Stanley S. Scott Cancer Center and Department of Otolaryngology, 533 Bolivar St. 5th Floor, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
Chattopadhyay
Ranajoy
R
Naidu
C V
CV
Izumi
Tadahide
T
D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D004249:DNA Damage / Q000502:physiology*; D004260:DNA Repair / Q000502:physiology*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D014162:Transfection
D011506:Proteins; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C486216:Apex1 protein, mouse; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase