Special Issue "Molecular Role of PARP in Health and Disease"

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

Deadline for manuscript submissions: closed (10 June 2019).

Special Issue Editor

Prof. Dr. Péter Bay
E-Mail Website
Guest Editor
Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, H-4032, Hungary
Interests: poly(ADP-ribose)polymerase; PARP; mitochondria; sirtuin; metabolism
Special Issues and Collections in MDPI journals

Special Issue Information

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

Manuscript Submission Information

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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

Published Papers (9 papers)

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Research

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Open AccessArticle
Spontaneous Development of Dental Dysplasia in Aged Parp-1 Knockout Mice
Cells 2019, 8(10), 1157; https://doi.org/10.3390/cells8101157 - 27 Sep 2019
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 [...] Read more.
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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Open AccessArticle
Automodified Poly(ADP-Ribose) Polymerase Analysisto Monitor DNA Damagein Peripheral Lymphocytes of Floriculturists Occupationally Exposed to Pesticides
Cells 2019, 8(2), 137; https://doi.org/10.3390/cells8020137 - 08 Feb 2019
Cited by 1
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 [...] Read more.
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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Open AccessArticle
Diastereomeric Recognition of 5’,8-cyclo-2’-Deoxyadenosine Lesions by Human Poly(ADP-ribose) Polymerase 1 in a Biomimetic Model
Cells 2019, 8(2), 116; https://doi.org/10.3390/cells8020116 - 02 Feb 2019
Cited by 1
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 [...] Read more.
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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Open AccessReview
Role of APD-Ribosylation in Bone Health and Disease
Cells 2019, 8(10), 1201; https://doi.org/10.3390/cells8101201 - 05 Oct 2019
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, [...] Read more.
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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Open AccessReview
The Role of PARPs in Inflammation—And Metabolic—Related Diseases: Molecular Mechanisms and Beyond
Cells 2019, 8(9), 1047; https://doi.org/10.3390/cells8091047 - 06 Sep 2019
Cited by 1
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 [...] Read more.
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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Open AccessReview
Regulation of Glucose Metabolism by NAD+ and ADP-Ribosylation
Cells 2019, 8(8), 890; https://doi.org/10.3390/cells8080890 - 13 Aug 2019
Cited by 1
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 [...] Read more.
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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Open AccessReview
Clinical Development of PARP Inhibitors in Treating Metastatic Castration-Resistant Prostate Cancer
Cells 2019, 8(8), 860; https://doi.org/10.3390/cells8080860 - 09 Aug 2019
Cited by 1
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 [...] Read more.
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)
Open AccessReview
Tankyrase (PARP5) Inhibition Induces Bone Loss through Accumulation of Its Substrate SH3BP2
Cells 2019, 8(2), 195; https://doi.org/10.3390/cells8020195 - 22 Feb 2019
Cited by 4
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 [...] Read more.
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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Other

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Open AccessErratum
Erratum: Hopp, A.K., et al. Regulation of Glucose Metabolism by NAD+ and ADP-Ribosylation. Cells 2019, 8, 890
Cells 2019, 8(11), 1371; https://doi.org/10.3390/cells8111371 - 31 Oct 2019
Abstract
Change in References list order. [...] Full article
(This article belongs to the Special Issue Molecular Role of PARP in Health and Disease)
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