On PAR with PARP: cellular stress signaling through poly(ADP-ribose) and PARP-1

Abstract

Cellular stress responses are mediated through a series of regulatory processes that occur at the genomic, transcriptional, post-transcriptional, translational, and posttranslational levels. These responses require a complex network of sensors and effectors from multiple signaling pathways, including the abundant and ubiquitous nuclear enzyme poly(ADP-ribose) (PAR) polymerase-1 (PARP-1). PARP-1 functions at the center of cellular stress responses, where it processes diverse signals and, in response, directs cells to specific fates (e.g., DNA repair vs. cell death) based on the type and strength of the stress stimulus. Many of PARP-1's functions in stress response pathways are mediated by its regulated synthesis of PAR, a negatively charged polymer, using NAD + as a donor of ADP-ribose units. Thus, PARP-1's functions are intimately tied to nuclear NAD + metabolism and the broader metabolic profile of the cell. Recent studies in cell and animal models have highlighted the roles of PARP-1 and PAR in the response to a wide variety of extrinsic and intrinsic stress signals, including those initiated by oxidative, nitrosative, genotoxic, oncogenic, thermal, inflammatory, and metabolic stresses. These responses underlie pathological conditions, including cancer, inflammation-related diseases, and metabolic dysregulation. The development of PARP inhibitors is being pursued as a therapeutic approach to these conditions. In this review, we highlight the newest findings about PARP-1's role in stress responses in the context of the historical data.Poly(ADP-ribose) (PAR) polymerase-1 (PARP-1) is the most abundant and ubiquitous member of a family of 17 related mammalian proteins. Studies over the past two decades, complemented by some exciting recent reports, have begun to crystallize a clearer view of one of the most robust and consistent functions of PARP-1 across biological systems: as a stress sensor and a stress response mediator. In this review, we highlight the newest findings in this area in the context of the historical data. We did not attempt to provide a comprehensive review, but rather opted to focus on key findings that have clarified the role of PARP-1 (and related PARPs) in stress responses. The reader is directed to a variety of other excellent reviews that cover other aspects of PARP-1 biology (D

Induction of Mitochondrial Dysfunction by Poly(ADP-Ribose) Polymer: Implication for Neuronal Cell Death

“…A substantial amount of PAR polymer is produced in response to a variety of toxic conditions in which PARP-1 plays an important role (Luo and Kraus, 2012). Previous studies revealed that PAR polymer can serve as an AIF-releasing factor and death signal .…”

FAF1 mediates regulated necrosis through PARP1 activation upon oxidative stress leading to dopaminergic neurodegeneration

“…PARP1 activators are typically enzymes, including kinases and acetyltransferases. 9 The posttranslational modifications of PARP1 by these enzymes often promote its catalytic activity. However, some proteins, such as aminoacyl tRNA synthetase complex-interacting multifunctional protein 2 (AIMP2) and glyceraldehyde-3-phosphate FAF1 acts as a parthanatos mediator C Yu et al dehydrogenase (GAPDH), activate PARP1 through physical interactions.…”

“…8 PARP1 has an N-terminal DNA-binding domain, a central automodification domain and a C-terminal catalytic domain. 9 PARP1 has a crucial role in the DNA damage surveillance network after oxidative stress. In response to mild DNA damage, PARP1 recognizes and binds to breaks in the DNA and catalyzes the covalent attachment of poly(ADP-ribose) (PAR) chains to acceptor proteins, including histones, DNA repair proteins and PARP1 itself.…”

“…In response to mild DNA damage, PARP1 recognizes and binds to breaks in the DNA and catalyzes the covalent attachment of poly(ADP-ribose) (PAR) chains to acceptor proteins, including histones, DNA repair proteins and PARP1 itself. 9,10 Subsequently, PARP1 recruits the proteins to sites of DNA damage, thereby maintaining genome stability and cellular homeostasis.…”

NAD+ in DNA repair and mitochondrial maintenance

“…In response to DNA damage, the rate of PAR synthesis increases rapidly up to 500-fold which can consume a significant amount of NAD C . 7 In the NM signaling cascade, the pathways critically affected by PARP1-dependent depletion of intracellular NAD C are SIRT1-dependent protein deacetylation, mitochondrial oxidative phosphorylation and mitophagy, the selective clearance of damaged or defective mitochondria. SIRT1 is a multifunctional protein deacetylase which plays important roles in cellular pathways including: longevity, metabolism, cellular senescence, genome maintenance, DNA repair, and inflammation.…”