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Critical role of poly(ADP‐ribose) polymerase‐1 in modulating the mode of cell death caused by continuous oxidative stress
Author(s) -
Son YoungOk,
Kook SungHo,
Jang YongSuk,
Shi Xianglin,
Lee JeongChae
Publication year - 2009
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.22332
Subject(s) - poly adp ribose polymerase , programmed cell death , apoptosis , transfection , dna damage , oxidative stress , microbiology and biotechnology , polymerase , apoptosis inducing factor , mitochondrion , chemistry , caspase , biology , biochemistry , dna , gene
Continuously generated hydrogen peroxide (H 2 O 2 ) inhibits typical apoptosis and instead initiates a caspase‐independent, apoptosis‐inducing factor (AIF)‐mediated pyknotic cell death. This may be related to H 2 O 2 ‐mediated DNA damage and subsequent ATP depletion, although the exact mechanisms by which the mode of cell death is decided after H 2 O 2 exposure are still unclear. Accumulated evidence and our previous data led us to hypothesize that continuously generated H 2 O 2 , not an H 2 O 2 bolus, induces severe DNA damage, signaling poly(ADP‐ribose) polymerase‐1 (PARP‐1) activation, ATP depletion, and eventually caspase‐independent cell death. Results from the present study support that H 2 O 2 generated continuously by glucose oxidase causes excessive DNA damage and PARP‐1 activation. Blockage of PARP‐1 by a siRNA transfection or by pharmacological inhibitor resulted in the significant inhibition of ATP depletion, loss of mitochondrial membrane potential, nuclear translocation of AIF and endonuclease G, and eventually conversion to caspase‐dependent apoptosis. Overall, the current study demonstrates the different roles of PARP‐1 inhibition in modulation of cell death according to the method of H 2 O 2 exposure, that is, continuous generation versus a direct addition. J. Cell. Biochem. 108: 989–997, 2009. © 2009 Wiley‐Liss, Inc.