title: Poly(ADP-ribose) signaling in cell death.
abstract: Poly(ADP-ribosyl)ation (PARylation) is a reversible protein modification carried out by the concerted actions of poly(ADP-ribose) polymerase (PARP) enzymes and poly(ADP-ribose) (PAR) decomposing enzymes such as PAR glycohydrolase (PARG) and ADP-ribosyl hydrolase 3 (ARH3). Reversible PARylation is a pleiotropic regulator of various cellular functions but uncontrolled PARP activation may also lead to cell death. The cellular demise pathway mediated by PARylation in oxidatively stressed cells has been described almost thirty years ago. However, the underlying molecular mechanisms have only begun to emerge relatively recently. PARylation has been implicated in necroptosis, autophagic cell death but its role in extrinsic and intrinsic apoptosis appears to be less predominant and depends largely on the cellular model used. Currently, three major pathways have been made responsible for PARP-mediated necroptotic cell death: (1) compromised cellular energetics mainly due to depletion of NAD, the substrate of PARPs; (2) PAR mediated translocation of apoptosis inducing factor (AIF) from mitochondria to nucleus (parthanatos) and (3) a mostly elusive crosstalk between PARylation and cell death/survival kinases and phosphatases. Here we review how these PARP-mediated necroptotic pathways are intertwined, how PARylation may contribute to extrinsic and intrinsic apoptosis and discuss recent developments on the role of PARylation in autophagy and autophagic cell death.
authors: Department of Medical Chemistry, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary; MTA DE Cell Biology and Signaling Research Group, Debrecen, Hungary. Electronic address: lvirag@med.unideb.hu.
authors: László
authors: L
authors: Virág
authors: Agnieszka
authors: A
authors: Robaszkiewicz
authors: Jose Manuel
authors: JM
authors: Rodriguez-Vargas
authors: Francisco Javier
authors: FJ
authors: Oliver
mesh_terms: D000818:Animals; D016923:Cell Death / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks / Q000502:physiology; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction
chemical_list: D011064:Poly Adenosine Diphosphate Ribose; D011065:Poly(ADP-ribose) Polymerases
keywords: Apoptosis; Autophagy; Cell death; Necroptosis; Necrosis; Oxidative stress; Poly(ADP-ribose) glycohydrolase; Poly(ADP-ribose) polymerase