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...

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Bibliographic Details
Published in:Toxicology (Amsterdam) 2006-07, Vol.224 (1), p.44-55
Main Authors: Peddi, Srinivasa R., Chattopadhyay, Ranajoy, Naidu, C.V., Izumi, Tadahide
Format: Article
Language:English
Subjects:
Animals
AP endonuclease
Binding, Competitive
Biological and medical sciences
Cell Line
DNA base excision repair
DNA Damage - physiology
DNA Repair - physiology
DNA-(Apurinic or Apyrimidinic Site) Lyase - genetics
DNA-(Apurinic or Apyrimidinic Site) Lyase - metabolism
Electrophoretic Mobility Shift Assay
Enzyme Activation - physiology
HeLa Cells
Humans
Medical sciences
Mice
Necrosis
Oxidative stress
PARP1
Poly (ADP-Ribose) Polymerase-1
Poly(ADP-ribose) Polymerases - genetics
Poly(ADP-ribose) Polymerases - metabolism
Proteins - metabolism
Toxicology
Transfection
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Summary: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 H 2O 2 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.
ISSN:0300-483X
1879-3185
DOI:10.1016/j.tox.2006.04.025