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Molecular Role of PARP in Health and Disease

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A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (10 June 2019) | Viewed by 72869

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Prof. Dr. Péter Bay

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Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary
Interests: poly(ADP-ribose)polymerase; PARP; mitochondria; sirtuin; metabolism
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

Poly(ADP-ribose) polymerases (PARPs or ARTDs) represent a 17-member family characterized by a common catalytic subunit. PARPs use NAD+ as substrate and PARP1 or PARP2, when activated can limit NAD+ availability in cells to other enzymes. PARPs and their product, poly(ADP-ribose) regulates transcription and chromatin structure. PARP enzymes have crucial role in regulating DNA repair making major PARP enzymes attractive targets for pharmacological inhibition. In the past few years, PARP inhibitors have entered the clinical use, while at the same time, more specific PARP inhibitors are being develop to target only tankyrases or mono-ADP-ribose polymerases among the PARP family members. In addition to DNA repair and oncological transformation, PARPs influence a plethora of other cellular (patho)physiological processes from metabolism to virus–host interactions.

Dr. Péter Bay
Guest Editor

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Keywords

PARP
ARTD
PARP inhibitors
PARylation
MARylation
macrodomain
olaparib
rucaparib
niraparib
chromatin
transcription
protein degradation
postrranslational modifications
DNA repair
cell division
hetarochromatin
cell cycle
tumor
neoplasia
cytostatic treatment
synthetic lethality
enzyme trapping
mitochondria
cell death
oxidative stress
inflammation
viral infection
energy sensors
circadian rhtythm
metabolic diseases
aging

Related Special Issue

Molecular Role of PARP in Health and Disease 2020 in Cells (8 articles)

Published Papers (12 papers)

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Research

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21 pages, 7294 KiB

Open AccessArticle

Silencing of PARP2 Blocks Autophagic Degradation

by Laura Jankó, Zsanett Sári, Tünde Kovács, Gréta Kis, Magdolna Szántó, Miklós Antal, Gábor Juhász and Péter Bai

Cells 2020, 9(2), 380; https://doi.org/10.3390/cells9020380 - 07 Feb 2020

Cited by 13 | Viewed by 4849

Abstract

Poly(ADP-Ribose) polymerases (PARPs) are enzymes that metabolize NAD⁺. PARP1 and PARP10 were previously implicated in the regulation of autophagy. Here we showed that cytosolic electron-dense particles appear in the cytoplasm of C2C12 myoblasts in which PARP2 is silenced by shRNA. The cytosolic electron-dense bodies resemble autophagic vesicles and, in line with that, we observed an increased number of LC3-positive and Lysotracker-stained vesicles. Silencing of PARP2 did not influence the maximal number of LC3-positive vesicles seen upon chloroquine treatment or serum starvation, suggesting that the absence of PARP2 inhibits autophagic breakdown. Silencing of PARP2 inhibited the activity of AMP-activated kinase (AMPK) and the mammalian target of rapamycin complex 2 (mTORC2). Treatment of PARP2-silenced C2C12 cells with AICAR, an AMPK activator, nicotinamide-riboside (an NAD⁺ precursor), or EX-527 (a SIRT1 inhibitor) decreased the number of LC3-positive vesicles cells to similar levels as in control (scPARP2) cells, suggesting that these pathways inhibit autophagic flux upon PARP2 silencing. We observed a similar increase in the number of LC3 vesicles in primary PARP2 knockout murine embryonic fibroblasts. We provided evidence that the enzymatic activity of PARP2 is important in regulating autophagy. Finally, we showed that the silencing of PARP2 induces myoblast differentiation. Taken together, PARP2 is a positive regulator of autophagic breakdown in mammalian transformed cells and its absence blocks the progression of autophagy. Full article

(This article belongs to the Special Issue Molecular Role of PARP in Health and Disease)

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17 pages, 5098 KiB

Open AccessArticle

Spontaneous Development of Dental Dysplasia in Aged Parp-1 Knockout Mice

by Hisako Fujihara, Tadashige Nozaki, Masahiro Tsutsumi, Mayu Isumi, Shinji Shimoda, Yoshiki Hamada and Mitsuko Masutani

Cells 2019, 8(10), 1157; https://doi.org/10.3390/cells8101157 - 27 Sep 2019

Cited by 3 | Viewed by 3376

Abstract

Poly(ADP-ribose) polymerase (Parp)-1 catalyzes polyADP-ribosylation using NAD⁺ and is involved in the DNA damage response, genome stability, and transcription. In this study, we demonstrated that aged Parp-1^−/− mouse incisors showed more frequent dental dysplasia in both ICR/129Sv mixed background and C57BL/6 strain compared to aged Parp-1^+/+ incisors, suggesting that Parp-1 deficiency could be involved in development of dental dysplasia at an advanced age. Computed tomography images confirmed that dental dysplasia was observed at significantly higher incidences in Parp-1^−/− mice. The relative calcification levels of Parp-1^−/− incisors were higher in both enamel and dentin (p < 0.05). Immunohistochemical analysis revealed (1) Parp-1 positivity in ameloblasts and odontoblasts in Parp-1^+/+ incisor, (2) weaker dentin sialoprotein positivity in dentin of Parp-1^−/− incisor, and (3) bone sialoprotein positivity in dentin of Parp-1^−/− incisor, suggesting ectopic osteogenic formation in dentin of Parp-1^−/− incisor. These results indicate that Parp-1 deficiency promotes odontogenic failure in incisors at an advanced age. Parp-1 deficiency did not affect dentinogenesis during the development of mice, suggesting that Parp-1 is not essential in dentinogenesis during development but is possibly involved in the regulation of continuous dentinogenesis in the incisors at an advanced age. Full article

(This article belongs to the Special Issue Molecular Role of PARP in Health and Disease)

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14 pages, 3036 KiB

Open AccessArticle

Automodified Poly(ADP-Ribose) Polymerase Analysisto Monitor DNA Damagein Peripheral Lymphocytes of Floriculturists Occupationally Exposed to Pesticides

by Serena Imperato, Carmela Mistretta, Maria Marone, Ilaria Migliaccio, Ilaria Pulcinelli and Maria Rosaria Faraone Mennella

Cells 2019, 8(2), 137; https://doi.org/10.3390/cells8020137 - 08 Feb 2019

Cited by 6 | Viewed by 3016

Abstract

Increased DNA damage and the propension to cancer development, depend on the modulation of the mechanisms to control and maintain genomic integrity. Poly(ADP-Ribose)Polymerase activation and automodification are early responses to genotoxic stress. Upon binding to DNA strand breaks, the enzyme, a molecular DNA nick sensor, is hyperactivated: this is the first step in a series of events leading to either DNA repair or apoptosis. Enzyme hyperactivation and automodification can be easily measured and are widely used to look at DNA damage extent in the cell. We investigated whether these two markers (increased catalytic activity and auto modification), could help to monitor DNA damage in lymphocytes of flower growers from Southern Italy, occupationally exposed to pesticides. Peripheral lymphocyte lysates were analyzed for Poly(ADP-Ribose)Polymerase activity, and by SDS-PAGE and anti-Poly(ADP-Ribose)Polymerase 1-antibodyto measure automodified Poly(ADP-Ribose)Polymerase levels bydensitometry. Poly(ADP-Ribose)Polymerase activity and PARP automodification followed the same trend. Growers daily exposed to pesticides, showed both biomarkers very high, either in the presence or in the absence of pathologies. PARP activity and auto-modification in peripheral blood lymphocytes are possible, non-invasive, androutinartools to monitor the healthy conditions of floricoltorists. Full article

(This article belongs to the Special Issue Molecular Role of PARP in Health and Disease)

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14 pages, 1668 KiB

Open AccessArticle

Diastereomeric Recognition of 5’,8-cyclo-2’-Deoxyadenosine Lesions by Human Poly(ADP-ribose) Polymerase 1 in a Biomimetic Model

by Annalisa Masi, Arianna Sabbia, Carla Ferreri, Francesco Manoli, Yanhao Lai, Eduardo Laverde, Yuan Liu, Marios G. Krokidis, Chryssostomos Chatgilialoglu and Maria Rosaria Faraone Mennella

Cells 2019, 8(2), 116; https://doi.org/10.3390/cells8020116 - 02 Feb 2019

Cited by 9 | Viewed by 3295

Abstract

5’,8-Cyclo-2’-deoxyadenosine (cdA), in the 5’R and 5’Sdiastereomeric forms, are typical non strand-break oxidative DNA lesions, induced by hydroxyl radicals, with emerging importance as a molecular marker. These lesions are exclusively repaired by the nucleotide excision repair (NER) mechanism with a low efficiency, thus readily accumulating in the genome. Poly(ADP-ribose) polymerase1 (PARP1) acts as an early responder to DNA damage and plays a key role as a nick sensor in the maintenance of the integrity of the genome by recognizing nicked DNA. So far, it was unknown whether the two diastereomeric cdA lesions could induce specific PARP1 binding. Here, we provide the first evidence of PARP1 to selectively recognize the diastereomeric lesions of 5’S-cdA and 5’R-cdA in vitro as compared to deoxyadenosine in model DNA substrates (23-mers) by using circular dichroism, fluorescence spectroscopy, immunoblotting analysis, and gel mobility shift assay. Several features of the recognition of the damaged and undamaged oligonucleotides by PARP1 were characterized. Remarkably, PARP1 exhibits different affinities in binding to a double strand (ds) oligonucleotide, which incorporates cdA lesions in R and S diastereomeric form. In particular, PARP1 proved to bind oligonucleotides, including a 5’S-cdA, with a higher affinity constant for the 5’S lesion in a model of ds DNA than 5’R-cdA, showing different recognition patterns, also compared with undamaged dA. This new finding highlights the ability of PARP1 to recognize and differentiate the distorted DNA backbone in a biomimetic system caused by different diastereomeric forms of a cdA lesion. Full article

(This article belongs to the Special Issue Molecular Role of PARP in Health and Disease)

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Review

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20 pages, 1313 KiB

Open AccessReview

Multifaceted Role of PARP-1 in DNA Repair and Inflammation: Pathological and Therapeutic Implications in Cancer and Non-Cancer Diseases

by Simonetta Pazzaglia and Claudio Pioli

Cells 2020, 9(1), 41; https://doi.org/10.3390/cells9010041 - 22 Dec 2019

Cited by 122 | Viewed by 9344

Abstract

PARP-1 (poly(ADP-ribose)-polymerase 1), mainly known for its protective role in DNA repair, also regulates inflammatory processes. Notably, defects in DNA repair and chronic inflammation may both predispose to cancer development. On the other hand, inhibition of DNA repair and inflammatory responses can be beneficial in cancer therapy and PARP inhibitors are currently used for their lethal effects on tumor cells. Furthermore, excess of PARP-1 activity has been associated with many tumors and inflammation-related clinical conditions, including asthma, sepsis, arthritis, atherosclerosis, and neurodegenerative diseases, to name a few. Activation and inhibition of PARP represent, therefore, a double-edged sword that can be exploited for therapeutic purposes. In our review, we will discuss recent findings highlighting the composite multifaceted role of PARP-1 in cancer and inflammation-related diseases. Full article

(This article belongs to the Special Issue Molecular Role of PARP in Health and Disease)

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20 pages, 1317 KiB

Open AccessReview

The Enigmatic Function of PARP1: From PARylation Activity to PAR Readers

by Tatiana Kamaletdinova, Zahra Fanaei-Kahrani and Zhao-Qi Wang

Cells 2019, 8(12), 1625; https://doi.org/10.3390/cells8121625 - 12 Dec 2019

Cited by 79 | Viewed by 9274

Abstract

Poly(ADP-ribosyl)ation (PARylation) is catalysed by poly(ADP-ribose) polymerases (PARPs, also known as ARTDs) and then rapidly removed by degrading enzymes. Poly(ADP-ribose) (PAR) is produced from PARylation and provides a delicate and spatiotemporal interaction scaffold for numerous target proteins. The PARylation system, consisting of PAR synthesizers and erasers and PAR itself and readers, plays diverse roles in the DNA damage response (DDR), DNA repair, transcription, replication, chromatin remodeling, metabolism, and cell death. Despite great efforts by scientists in biochemistry, cell and molecular biology, genetics, and pharmacology over the last five decades, the biology of PARPs and PARylation remains enigmatic. In this review, we summarize the current understanding of the biological function of PARP1 (ARTD1), the founding member of the PARP family, focusing on the inter-dependent or -independent nature of different functional domains of the PARP1 protein. We also discuss the readers of PAR, whose function may transduce signals and coordinate the cellular processes, which has recently emerged as a new research avenue for PARP biology. We aim to provide some perspective on how future research might disentangle the biology of PARylation by dissecting the structural and functional relationship of PARP1, a major effector of the PARPs family. Full article

(This article belongs to the Special Issue Molecular Role of PARP in Health and Disease)

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15 pages, 1061 KiB

Open AccessReview

Role of APD-Ribosylation in Bone Health and Disease

by Chun Wang and Gabriel Mbalaviele

Cells 2019, 8(10), 1201; https://doi.org/10.3390/cells8101201 - 05 Oct 2019

Cited by 6 | Viewed by 3898

Abstract

The transfer of adenosine diphosphate (ADP)-ribose unit(s) from nicotinamide adenine dinucleotide (NAD⁺) to acceptor proteins is known as ADP-ribosylation. This post-translational modification (PTM) unavoidably alters protein functions and signaling networks, thereby impacting cell behaviors and tissue outcomes. As a ubiquitous mechanism, ADP-ribosylation affects multiple tissues, including bones, as abnormal ADP-ribosylation compromises bone development and remodeling. In this review, we describe the effects of ADP-ribosylation in bone development and maintenance, and highlight the underlying mechanisms. Full article

(This article belongs to the Special Issue Molecular Role of PARP in Health and Disease)

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22 pages, 2615 KiB

Open AccessReview

The Role of PARPs in Inflammation—And Metabolic—Related Diseases: Molecular Mechanisms and Beyond

by Yueshuang Ke, Chenxin Wang, Jiaqi Zhang, Xiyue Zhong, Ruoxi Wang, Xianlu Zeng and Xueqing Ba

Cells 2019, 8(9), 1047; https://doi.org/10.3390/cells8091047 - 06 Sep 2019

Cited by 68 | Viewed by 6891

Abstract

Poly(ADP-ribosyl)ation (PARylation) is an essential post-translational modification catalyzed by poly(ADP-ribose) polymerase (PARP) enzymes. Poly(ADP-ribose) polymerase 1 (PARP1) is a well-characterized member of the PARP family. PARP1 plays a crucial role in multiple biological processes and PARP1 activation contributes to the development of various inflammatory and malignant disorders, including lung inflammatory disorders, cardiovascular disease, ovarian cancer, breast cancer, and diabetes. In this review, we will focus on the role and molecular mechanisms of PARPs enzymes in inflammation- and metabolic-related diseases. Specifically, we discuss the molecular mechanisms and signaling pathways that PARP1 is associated with in the regulation of pathogenesis. Recently, increasing evidence suggests that PARP inhibition is a promising strategy for intervention of some diseases. Thus, our in-depth understanding of the mechanism of how PARPs are activated and how their signaling downstream effecters can provide more potential therapeutic targets for the treatment of the related diseases in the future is crucial. Full article

(This article belongs to the Special Issue Molecular Role of PARP in Health and Disease)

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23 pages, 1493 KiB

Open AccessReview

Regulation of Glucose Metabolism by NAD⁺ and ADP-Ribosylation

by Ann-Katrin Hopp, Patrick Grüter and Michael O. Hottiger

Cells 2019, 8(8), 890; https://doi.org/10.3390/cells8080890 - 13 Aug 2019

Cited by 52 | Viewed by 12852

Abstract

Cells constantly adapt their metabolic pathways to meet their energy needs and respond to nutrient availability. During the last two decades, it has become increasingly clear that NAD⁺, a coenzyme in redox reactions, also mediates several ubiquitous cell signaling processes. Protein ADP-ribosylation is a post-translational modification that uses NAD⁺ as a substrate and is best known as part of the genotoxic stress response. However, there is increasing evidence that NAD⁺-dependent ADP-ribosylation regulates other cellular processes, including metabolic pathways. In this review, we will describe the compartmentalized regulation of NAD⁺ biosynthesis, consumption, and regeneration with a particular focus on the role of ADP-ribosylation in the regulation of glucose metabolism in different cellular compartments. Full article

(This article belongs to the Special Issue Molecular Role of PARP in Health and Disease)

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12 pages, 1011 KiB

Open AccessReview

Clinical Development of PARP Inhibitors in Treating Metastatic Castration-Resistant Prostate Cancer

by Jacob J. Adashek, Rohit K. Jain and Jingsong Zhang

Cells 2019, 8(8), 860; https://doi.org/10.3390/cells8080860 - 09 Aug 2019

Cited by 38 | Viewed by 6887

Abstract

The approval of upfront abiraterone for castration-sensitive prostate cancer and the approval of enzalutamide and apalutamide for non-metastatic castration-resistant prostate cancer have led to early utilization of potent androgen receptor (AR) signaling inhibitors in treating advanced prostate cancer. There is an unmet need to develop novel therapies beyond targeting AR signaling for metastatic castration-resistant prostate cancer (mCRPC). Poly (ADP-ribose) polymerase inhibitors (PARPi) belong to a class of targeted agents being developed for the treatment of homologous recombination repair (HRR) deficient tumors. Olaparib, rucaparib, niraparib, veliparib, and talazoparib were evaluated in early phase trials as a monotherapy for HRR-deficient mCRPC. Among them, olaparib and rucaparib have breakthrough designations for BRCA1/2-mutated mCRPC. Phase II studies also reported clinical activity of the PARPi and abiraterone combination and the PARPi checkpoint inhibitor combination in HRR-intact mCRPC. Ongoing phase III trials are testing these combinations as frontline or later line treatments for mCRPC. This review summarizes the critical clinical data as well as ongoing clinical trials for developing PARPi in treating mCRPC. Full article

(This article belongs to the Special Issue Molecular Role of PARP in Health and Disease)

14 pages, 1534 KiB

Open AccessReview

Tankyrase (PARP5) Inhibition Induces Bone Loss through Accumulation of Its Substrate SH3BP2

by Tomoyuki Mukai, Shunichi Fujita and Yoshitaka Morita

Cells 2019, 8(2), 195; https://doi.org/10.3390/cells8020195 - 22 Feb 2019

Cited by 20 | Viewed by 6042

Abstract

There is considerable interest in tankyrase because of its potential use in cancer therapy. Tankyrase catalyzes the ADP-ribosylation of a variety of target proteins and regulates various cellular processes. The anti-cancer effects of tankyrase inhibitors are mainly due to their suppression of Wnt signaling and inhibition of telomerase activity, which are mediated by AXIN and TRF1 stabilization, respectively. In this review, we describe the underappreciated effects of another substrate, SH3 domain-binding protein 2 (SH3BP2). Specifically, SH3BP2 is an adaptor protein that regulates intracellular signaling pathways. Additionally, in the human genetic disorder cherubism, the gain-of-function mutations in SH3BP2 enhance osteoclastogenesis. The pharmacological inhibition of tankyrase in mice induces bone loss through the accumulation of SH3BP2 and the subsequent increase in osteoclast formation. These findings reveal the novel functions of tankyrase influencing bone homeostasis, and imply that tankyrase inhibitor treatments in a clinical setting may be associated with adverse effects on bone mass. Full article

(This article belongs to the Special Issue Molecular Role of PARP in Health and Disease)

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