Poly(ADP-ribose) catabolism in mammalian cells exposed to DNA-damaging agents

Alvarez-Gonzalez, Rafael; Althaus, Felix R.

doi:10.1016/0921-8777(89)90012-8

Cited by 204 publications

(137 citation statements)

References 31 publications

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“…When DNA is damaged by H 2 O 2 , the accumulated PAR undergoes rapid turnover, with a half-life of less than 1 min, and is converted into mono(ADPR) by PARG. 13,30,31 The partial inhibitory effect of 3-AB/DPQ on the Na þ /Ca 2 þ influx ( Figure 5B) therefore suggests that mono(ADPR) is probably produced by PARG, resulting in TRPM2 opening. However, other explanations cannot be ruled out.…”

Section: Discussionmentioning

confidence: 96%

“…H 2 O 2 ), the enzyme poly(ADP-ribose) glycohydrolase (PARG) converts PAR (half-life of less than 1 min) into mono(-ADPR). 13,30,31 Since anti-PAR antibody only recognizes the polymer, 32 to prevent PAR degradation into ADPR, the cells were fixed with trichloroacetic acid (see Supplementary Methods). Compared to the untreated control (Figure 1Ea), a marked increase in nuclear PAR immunoreactivity was seen in myocytes exposed for 5-20 min to 20 or 100 mM …”

Section: H 2 O 2 Increases Intracellular Levels Of Nad þ and Adprmentioning

confidence: 99%

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Activation of the transient receptor potential M2 channel and poly(ADP-ribose) polymerase is involved in oxidative stress-induced cardiomyocyte death

et al. 2005

Cell Death Differ

107

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Overproduction of reactive oxygen species is one of the major causes of cell death in ischemic-reperfusion (I/R) injury. In I/R animal models, electron microscopy (EM) has shown mixed apoptotic and necrotic characteristics in the same cardiomyocyte. The present study shows that H 2 O 2 activates both apoptotic and necrotic machineries in the same myocyte and that the ultrastructure seen using EM is very similar to that in I/R animal studies. The apoptotic component is caused by the activation of clotrimazole-sensitive, NAD þ /ADP ribose/poly (ADP-ribose) polymerase (PARP)-dependent transient receptor potential M2 (TRPM2) channels, which induces mitochondrial [Na þ ] m (and [Ca 2 þ ] m ) overload, resulting in mitochondrial membrane disruption, cytochrome c release, and caspase 3-dependent chromatin condensation/fragmentation. The necrotic component is caspase 3-independent and is caused by PARP-induced [ATP] i /NAD þ depletion, resulting in membrane permeabilization. Inhibition of either TRPM2 or PARP activity only partially inhibits cell death, while inhibition of both completely prevents the ultrastructural changes and myocyte death.

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Section: Discussionmentioning

confidence: 96%

Section: H 2 O 2 Increases Intracellular Levels Of Nad þ and Adprmentioning

confidence: 99%

Activation of the transient receptor potential M2 channel and poly(ADP-ribose) polymerase is involved in oxidative stress-induced cardiomyocyte death

et al. 2005

Cell Death Differ

107

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“…29,30 As soon as the level of poly(ADP-ribose) exceeds a threshold (approximately 5 mM), cytoplasmic PARG is recruited to the nucleus. 31 PARG hydrolyses the protein-bound poly(ADP-ribose), thereby generating free oligo-and monomers of ADP-ribose. 30 This indicates that PARP-1 and PARG activities in response to DNA damage are closely coordinated.…”

Section: Discussionmentioning

confidence: 99%

UV irradiation inhibits ABC transporters via generation of ADP-ribose by concerted action of poly(ADP-ribose) polymerase-1 and glycohydrolase

et al. 2003

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ATP-binding cassette (ABC) transporters are involved in the transport of multiple substrates across cellular membranes, including metabolites, proteins, and drugs. Employing a functional fluorochrome export assay, we found that UVB irradiation strongly inhibits the activity of ABC transporters. Specific inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1) restored the function of ABC transporters in UVB-irradiated cells, and PARP-1-deficient cells did not undergo UVBinduced membrane transport inhibition. These data suggest that PARP-1 activation is necessary for ABC transporter functional downregulation. The hydrolysis of poly(ADPribose) by poly(ADP-ribose) glycohydrolase (PARG) was also required, since specific PARG inhibitors, which limit the production of ADP-ribose molecules, restored the function of ABC transporters. Furthermore, ADP-ribose molecules potently inhibited the activity of the ABC transporter Pglycoprotein. Hence, poly(ADP-ribose) metabolism appears to play a novel role in the regulation of ABC transporters.

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“…The major product of PAR degradation is ADP-ribose (Fig. 1A, lane 1) arising from the activity of poly(ADP-ribose) glycohydrolase activity present in nuclear extracts (24,25). In the presence of 1 mM deoxynucleotides (dNTPs), which allowed nick-induced DNA synthesis, in addition to radiolabeled ADP-ribose and AMP, labeled ATP was detected (Fig.…”

Section: Resultsmentioning

confidence: 99%

ATP for the DNA Ligation Step in Base Excision Repair Is Generated from Poly(ADP-ribose)

Oei

Ziegler

2000

Journal of Biological Chemistry

133

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In mammalian cells, the base excision repair (BER) pathway is the main route to counteract the mutagenic effects of DNA lesions. DNA nicks induce, among others, DNA polymerase activities and the synthesis of poly-(ADP-ribose). It is shown here that poly(ADP-ribose) serves as an energy source for the final and rate-limiting step of BER, DNA ligation. This conclusion was drawn from experiments in which the fate of [ 32 P]poly(ADPribose) or [ 32 P]NAD added to HeLa nuclear extracts was systematically followed. ATP was synthesized from poly-(ADP-ribose) in a pathway that strictly depended on nick-induced DNA synthesis. NAD was used for the synthesis of poly(ADP-ribose), which, in turn, was converted to ATP by pyrophosphorylytic cleavage utilizing the pyrophosphate generated from dNTPs during DNA synthesis. The adenylyl moiety was then preferentially used to adenylate DNA ligase III, from which it was transferred to the 5 -phosphoryl end of the nicked DNA. Finally, ligation to the 3 -OH end resulted in the release of AMP. When using NAD, but not poly(ADP-ribose), in the presence of 3-aminobenzamide, the entire process was blocked, confirming poly(ADP-ribosyl)ation to be the essential initial step. Thus, poly(ADP-ribose) polymerase-1, DNA polymerase ␤, and ligase III interact with x-ray repair cross-complementing protein-1 within the BER complex, which ensures that ATP is generated and specifically used for DNA ligation.The maintenance of an intact genome is crucial to each individual. Therefore, DNA damages need to be efficiently removed, which is accomplished by complex DNA repair mechanisms (reviewed in Ref. 1). The major pathway, BER, 1 is initiated by DNA glycosylases that cleave the base-deoxyribose glycosyl bond of a damaged nucleotide residue. Then, endonucleases are recruited that cleave the chain on the 5Ј side of the abasic site. As a result, nicked DNA intermediates occur. Nicked DNA, in turn, triggers the catalytic activities of DNA polymerase ␤ (Pol ␤) and poly(ADP-ribose) polymerase-1 (PARP-1) (2-4).Several different enzymes with poly(ADP-ribosyl)ation activity (EC 2.4.2.30) have been described recently, but the major cellular pathway of NAD catabolism in response to the appearance of DNA lesions has been ascribed to the catalytic activity of the 116-kDa protein reviewed in Ref. 5). Besides a potential participation of PARP-1 in transcription (6, 7), recombination, apoptosis, and necrosis (5), a large number of molecular and genetic studies have clearly implicated PARP-1 activity in positively regulating BER (8, 9). Originally, it was suggested that poly(ADP-ribosyl)ation may activate a DNA ligase required for DNA repair in mammalian cells (10). Several further investigations confirmed a positive influence of PARP-1 activity on DNA repair, especially on DNA ligation reviewed in Ref. 9). However, the actual function of PARP-1 in the BER process and the mechanism whereby poly(ADP-ribose) synthesis stimulates ligation (14) have still remained obscure (reviewed in Ref. 9). X-ray repair cross-complementing...

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Poly(ADP-ribose) catabolism in mammalian cells exposed to DNA-damaging agents

Cited by 204 publications

References 31 publications

Activation of the transient receptor potential M2 channel and poly(ADP-ribose) polymerase is involved in oxidative stress-induced cardiomyocyte death

Activation of the transient receptor potential M2 channel and poly(ADP-ribose) polymerase is involved in oxidative stress-induced cardiomyocyte death

UV irradiation inhibits ABC transporters via generation of ADP-ribose by concerted action of poly(ADP-ribose) polymerase-1 and glycohydrolase

ATP for the DNA Ligation Step in Base Excision Repair Is Generated from Poly(ADP-ribose)

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