The human apurinic/apyrimidinic endonuclease-1 suppresses activation of poly(adp-ribose) polymerase-1 induced by DNA single strand breaks

Srinivasa R. Peddi, Ranajoy Chattopadhyay, C. V. Naidu, Tadahide Izumi

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)44-55
Number of pages12
JournalToxicology
Volume224
Issue number1-2
DOIs
StatePublished - Jul 5 2006

Bibliographical note

Funding Information:
The authors would like to thank Drs. de Murcia for providing PARP1−/− cells, and Dr. J.W. Hill for his technical suggestion on EMSA; Drs. S. Mitra and A. Yasui for their critical discussions; and Dr. D. Konkel for his critical reading of the manuscript. Mrs. Q. Guo's technical assistance is also acknowledged. Finally, we are grateful for all of our colleagues who have been supportive for our recovery process after the hurricane disaster in 2005. This work was supported by NIH grants CA98664 and CA53791.

Keywords

  • AP endonuclease
  • DNA base excision repair
  • Necrosis
  • Oxidative stress
  • PARP1

ASJC Scopus subject areas

  • Toxicology

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