Modulation of poly(ADP-ribosylation) in apoptotic cells
Section snippets
Poly(ADP-ribosylation): a sensor of DNA damage
The poly(ADP-ribosylation) reaction, discovered 40 years ago [1], is a post-translational modification of proteins involved in DNA repair, replication, transcription and cell death [2], [3], [4], [5], [6]. Poly(ADP-ribose) metabolism is regulated by the concerted action of PARP and PARG. In the presence of DNA strand breaks, PARP-1 uses the substrate β-NAD+ for transferring ADP-ribose polymers to itself and to nuclear acceptor proteins. Polymers are rapidly removed by PARG, which catalyzes the
Poly(ADP-ribosylation) and apoptosis
Once activated, PARP-1 produces polymers of ADP-ribose, thus allowing the depletion of intracellular NAD+ and a fall in ATP. Cellular NAD+ regulates several vital cellular processes, and serves also as precursor for NADP, a cofactor for different synthetic pathways [6]. In this respect, years ago it was proposed that NAD consumption may lead to cell suicide [38]; in fact, intracellular ATP is relevant in driving the apoptotic response and to prevent necrosis [39], [40], [41].
During apoptosis, a
Protective effect of PARP inhibitors
Although poly(ADP-ribosylation) may be beneficial, a massive PARP-1 activation under damage conditions can be detrimental to the tissue because of energy depletion and consequent occurrence of necrotic death. PARP-1 inhibition by chemicals, by the antisense strategy, by creating dominant negative mutants or PARP-1−/− mice, could interfere with apoptosis to a different extent [10], [11], [12], [13], [59], [60], [61], [62], [63], [64], [65], possibly depending on the nature of the apoptogenic
Protective effect of PARG inhibitors
PARG regulates poly(ADP-ribose) turnover by releasing monomers of ADP-ribose and by shortening long polymers (exo/endo activity, Fig. 1) [84]. During apoptosis, PARG is a target of caspases [85], [86]. Since PARG inhibition could influence PARP-1-mediated cell death either by making poly(ADP-ribose) turnover slower or causing PARP-1 inhibition by massive PARP-1 autoribosylation, PARG is now considered as a cell death mediator [87]. Accordingly to this view, some compounds that inhibit PARG
Future perspectives
The assumption that poly(ADP-ribosylation) plays a crucial role in carcinogenesis (reviewed in [91]) legitimates the growing interest in developing PARP-1 and PARG inhibitors to improve the efficacy of radio- and chemo-therapy. Since PARP-1 shares the role of guardian of genome integrity with other factors, e.g. DNA-PK, a promising strategy for tumor sensitization could be represented by the combined use of inhibitors of PARP-1 and DNA-PK [92]. On the other hand, it is well known that many
Acknowledgements
Research at the laboratory of AIS is supported by the Italian CNR and MIUR (FIRB Project RBNE0132MY). MD’s work is supported by the “Fondation de Recherche Cancer et Sang”, the “Recherches Scientifiques Luxembourg” Association, Télévie (grant 7.4577.02) and “Een Häerz fir kriibskrank Kanner” Association.
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2022, Journal of Biological ChemistryContribution of poly(ADP-ribose)polymerase-1 activation and apoptosis in trichloroethene-mediated autoimmunity
2019, Toxicology and Applied PharmacologyCitation Excerpt :Thus, our findings not only suggest a potential role of PARP-1 activation in TCE-mediated autoimmunity, but also provide a clear rationale for evaluating apoptotic pathways leading to autoimmune responses. One of major outcomes resulting from PARP-1 activation is apoptosis leading to cell death (Abdelali et al., 2016; Ba and Garg, 2011; Ivana Scovassi and Diederich, 2004; Wang et al., 2016a, 2016b). Excessive ROS generation can induce cell apoptosis by triggering multiple pathways including the functions of caspase proteins (Ortona et al., 2014; Rosado et al., 2013; Trachootham et al., 2008).
Poly(ADP-ribose): A signaling molecule in different paradigms of cell death
2014, Biochemical PharmacologyCitation Excerpt :As illustrated in Fig. 2, the main enzyme involved in PAR synthesis, PARP-1 (113 kDa) is cleaved into two fragments, both unable to perform their enzymatic activity [9,10]. PARP-1 cleavage is the best hallmark of caspase-dependent apoptosis [9,10]. After the discovery of PARP-2, a DNA dependent PARP involved to a low extent in the damage response [1,3,11,12], an active research program aimed at depicting its role in cell death has been carried out.
Inflammation-induced DNA damage and damage-induced inflammation: A vicious cycle
2014, Microbes and InfectionCitation Excerpt :PARP-1 directly binds and recruits several proteins of the major repair pathways (MRE11, NBS1199,200, Ku70201, DNA-PK202, ATM203) and regulates chromatin remodelling, DNA replication and repair, and transcriptional activity of inflammatory factors204–206 (Fig. 1F). PARP-1 is also involved in caspase-1 mediated [73] or caspase-independent [74] apoptosis and autophagy207 [75]. PARP-1 catalyses the addition of poly (ADP-ribose) (PAR) chains to its substrate proteins and facilitates DNA repair.
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