Inhibition of DNA binding by the phosphorylation of poly ADP-ribose polymerase protein catalysed by protein kinase C

Bauer, Paul; Farkas, Gyöngyi; Buday, László; Mikala, Gábor; Mészáros, György; Kun, Ernest; Farago, Anna F.

doi:10.1016/0006-291x(92)91256-p

Cited by 44 publications

(29 citation statements)

References 29 publications

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“…Although the kinase was not identified, ERK1͞2 is a plausible candidate given that ERK1͞2 exhibits sustained activation during the oocyte maturation process (36). Evidence also suggests that PARP-1 may be phosphorylated by protein kinase C, with a resultant down-regulation of PARP-1 activity by that modification (37,38). The present results suggest that ERK1͞2 activation is a prerequisite for maximal PARP-1 activation after DNA damage.…”

Section: Discussionmentioning

confidence: 61%

Direct phosphorylation and regulation of poly(ADP-ribose) polymerase-1 by extracellular signal-regulated kinases 1/2

Kauppinen¹,

Chan²,

Suh³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

187

178

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Sustained activation of poly(ADP-ribose) polymerase-1 (PARP-1) and extracellular signal-regulated kinases 1͞2 (ERK1͞2) both promote neuronal death. Here we identify a direct link between these two cell death pathways. In a rat model of hypoglycemic brain injury, neuronal PARP-1 activation and subsequent neuronal death were blocked by the ERK1͞2 inhibitor 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD98059). In neuron cultures, PARP-1-mediated neuronal death induced by N-methyl-Daspartate, peroxynitrite, or DNA alkylation was similarly blocked by ERK1͞2 pathway inhibitors. These inhibitors also blocked PARP-1 activation and PARP-1-mediated death in astrocytes. siRNA down-regulation of ERK2 expression in astrocytes also blocked PARP-1 activation and cell death. Direct effects of ERK1͞2 on PARP-1 were evaluated by using isolated recombinant enzymes. The activity of recombinant human PARP-1 was reduced by incubation with alkaline phosphatase and restored by incubation with active ERK1 or ERK2. Putative ERK1͞2 phosphorylation sites on PARP-1 were identified by mass spectrometry. Using site-directed mutagenesis, these sites were replaced with alanine (S372A and T373A) to block phosphorylation, or with glutamate (S372E and T373E) to mimic constitutive phosphorylation. Transfection of PARP-1 deficient mouse embryonic fibroblasts with the mutant PARP-1 species showed that the S372A and T373A mutations impaired PARP-1 activation, whereas the S372E and T373E mutations increased PARP-1 activity and eliminated the effect of ERK1͞2 inhibitors on PARP-1 activation. These results suggest that PARP1 phosphorylation by ERK1͞2 is required for maximal PARP-1 activation after DNA damage.DNA damage ͉ hypoglycemia ͉ mitogen-activated protein kinase ͉ astrocyte ͉ neuron P oly(ADP-ribose) polymerase-1 (PARP-1) is an abundant nuclear enzyme that is activated by DNA strand breaks and functionally linked to DNA repair (1). PARP-1 activation in neurons occurs in ischemia, trauma, hypoglycemia, excitotoxicity, multiple sclerosis, and other conditions involving oxidative stress or inflammation (2-5). When activated, PARP-1 consumes NAD to form poly(ADP-ribose) (PAR) on specific acceptor proteins. The poly(ADP-ribosyl)ation modifies protein binding to DNA and other proteins to facilitate DNA repair and prevent chromatid exchange (1, 6). However, extensive activation of PARP-1 leads to NAD depletion and cell death (7-9). PARP inhibitors and PARP-1 gene deletion can markedly improve neuronal survival in ischemia and other disorders (10-12). PARP-1 also interacts with several transcription factors (13), and the coactivation of nuclear factor B (NF-B) by PARP-1 promotes the cellular inflammatory response (14-16).Like PARP-1, the extracellular signal-regulated kinases 1 and 2 (ERK1͞2) are activated by ischemia and other conditions that generate oxidative stress (17-22). ERK1͞2, p38, and c-Jun-Nterminal kinase (JNK) comprise the major subgroups of the mitogen-activated protein kinases (MAPKs) (23), which are serine͞ threonine kinases involved...

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Section: Discussionmentioning

confidence: 61%

Direct phosphorylation and regulation of poly(ADP-ribose) polymerase-1 by extracellular signal-regulated kinases 1/2

Kauppinen¹,

Chan²,

Suh³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

187

178

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“…Currently, several regulatory mechanisms of PARP-1 activity have been proposed: first, PARP auto-poly(ADP-ribosyl)ation as a negative model of modulation of PARP-1 activity and 32 second, phosphorylation of PARP-1 by a number of protein kinases, such as protein kinase C (PKC), DNA-dependent protein kinase (DNA-PK), AMP-activated protein kinase (AMPK), and ERK1/2. 25,33,34 In this study, we, for the first time, provide evidence showing that PARP-1 may serve as a substrate for JNK1. First, PARP-1 interacts with JNK1 in Figure 5 Nuclear translocation of activated JNK.…”

Section: Discussionmentioning

confidence: 65%

c-Jun N-terminal kinase mediates hydrogen peroxide-induced cell death via sustained poly(ADP-ribose) polymerase-1 activation

Zhang

Yan

et al. 2007

Cell Death Differ

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Reactive oxygen species (ROS) have been closely associated with both apoptotic and non-apoptotic/necrotic cell death. Our previous study has illustrated that c-Jun-N-terminal kinase 1 (JNK1) is the main executor in hydrogen peroxide (H 2 O 2 )-induced nonapoptotic cell death. The main objective of this study is to further elucidate the molecular mechanisms downstream of JNK1 in H 2 O 2 -induced cell death. In this study, poly(ADP-ribose) polymerase-1 (PARP-1), a key DNA repair protein, was readily activated by H 2 O 2 and inhibition of PARP-1 activation by either a pharmacological or genetic approach offered significant protection against H 2 O 2 -induced cell death. More importantly, H 2 O 2 -mediated PARP-1 activation is subject to regulation by JNK1. Suppression of JNK1 activation by a chemical inhibitor or genetic deletion markedly suppressed the late-phase PARP-1 activation induced by H 2 O 2 , suggesting that JNK1 contributes to the sustained activation of PARP-1. Such findings were supported by the temporal pattern of nuclear translocation of activated JNK and a direct protein-protein interaction between JNK1 and PARP-1 in H 2 O 2 -treated cells. Finally, in vitro kinase assay suggests that PARP-1 may serve as the direct phosphorylation target for JNK1. Taken together, data from our study reveal a novel underlying mechanism in H 2 O 2 -induced nonapoptotic cell death: JNK1 promotes a sustained PARP-1 activation via nuclear translocation, protein-protein interaction and PARP-1 phosphorylation.

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“…The binding of these enzymes to the same broken DNA molecule would increase the likelihood that DNA-PK could phosphorylate PARP and/or PARP could ADP-ribosylate DNA-PK in response to DNA damage. Interestingly, PARP has been shown previously to be a phosphoprotein (43), and the phosphorylation of PARP by protein kinase C reduces its DNA binding affinity and auto-ADP-ribosylation activity (44). However, preliminary data indicate the phosphorylation of PARP by DNA-PK has no obvious effect on PARP DNA binding or catalytic activity.…”

Section: A Lane D)mentioning

confidence: 97%

Stimulation of the DNA-dependent Protein Kinase by Poly(ADP-Ribose) Polymerase

Ruscetti¹,

Lehnert²,

Halbrook³

et al. 1998

Journal of Biological Chemistry

214

145

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The DNA-dependent protein kinase (DNA-PK) is a heterotrimeric enzyme that binds to double-stranded DNA and is required for the rejoining of double-stranded DNA breaks in mammalian cells. It has been proposed that DNA-PK functions in this DNA repair pathway by binding to the ends of broken DNA molecules and phosphorylating proteins that bind to the damaged DNA ends. Another enzyme that binds to DNA strand breaks and may also function in the cellular response to DNA damage is the poly(ADP-ribose) polymerase (PARP). Here, we show that PARP can be phosphorylated by purified DNA-PK, and the catalytic subunit of DNA-PK is ADP-ribosylated by PARP. The protein kinase activity of DNA-PK can be stimulated by PARP in the presence of NAD ؉ in a reaction that is blocked by the PARP inhibitor 1,5-dihydroxyisoquinoline. The stimulation of DNA-PK by PARP-mediated protein ADP-ribosylation occurs independent of the Ku70/80 complex. Taken together, these results show that PARP can modify the activity of DNA-PK in vitro and suggest that these enzymes may function coordinately in vivo in response to DNA damage.Biochemical pathways that function in the recognition and repair of DNA damage are critical for maintaining genomic integrity. Potentially devastating DNA damage in the form of double-strand breaks (DSBs) 1 can occur when cells are exposed to ionizing radiation, oxidative stress and radiomimetic drugs. The DNA-dependent protein kinase (DNA-PK) is a key component of DNA DSB rejoining pathways in mammalian cells. DNA-PK is a heterotrimeric enzyme complex comprised of a 460-kDa catalytic subunit (1) and a regulatory component consisting of the Ku70 and Ku80 proteins (2, 3). The Ku70 and Ku80 proteins form a heterodimeric complex that binds to the ends of double-stranded DNA with high affinity (4 -8). The catalytic subunit of DNA-PK (DNA-PKcs) binds to the Ku70/80 complex in the presence of double-stranded DNA (9) and phosphorylates a wide variety of protein substrates in vitro on serine and threonine residues (10, 11). The protein kinase activity of DNA-PK is autoregulatory; in the absence of a phosphorylation substrate, DNA-PKcs autophosphorylates and dissociates from the Ku70/80-DNA complex (12).Evidence that DNA-PK plays an integral role in the repair of DNA DSB has been provided through the characterization of rodent cell lines that have mutations that disrupt the expression of the Ku80 (13-19) or DNA-PKcs (20 -24). Although it is clear that DNA-PK is an important component of mammalian DNA DSB repair pathways, it is not known how the enzyme participates in these processes. In vitro, DNA-PK preferentially phosphorylates protein substrates that co-localize on the same DNA molecule (3,25). This suggests that the specificity of the phosphorylation reaction may be regulated, in part, via the co-localization of the enzyme and substrate target on DNA. Based on these data, it has been proposed that DNA-PK could participate in the DNA rejoining reaction by phosphorylating DNA repair factors that co-localize with it on broken DNA en...

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Inhibition of DNA binding by the phosphorylation of poly ADP-ribose polymerase protein catalysed by protein kinase C

Cited by 44 publications

References 29 publications

Direct phosphorylation and regulation of poly(ADP-ribose) polymerase-1 by extracellular signal-regulated kinases 1/2

Direct phosphorylation and regulation of poly(ADP-ribose) polymerase-1 by extracellular signal-regulated kinases 1/2

c-Jun N-terminal kinase mediates hydrogen peroxide-induced cell death via sustained poly(ADP-ribose) polymerase-1 activation

Stimulation of the DNA-dependent Protein Kinase by Poly(ADP-Ribose) Polymerase

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