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23 pages, 5720 KiB

Open AccessArticle

Silencing of Poly(ADP-Ribose) Polymerase-2 Induces Mitochondrial Reactive Species Production and Mitochondrial Fragmentation

by Laura Jankó, Tünde Kovács, Miklós Laczik, Zsanett Sári, Gyula Ujlaki, Gréta Kis, Ibolya Horváth, Miklós Antal, László Vígh, Bálint L. Bálint, Karen Uray and Péter Bai

Cells 2021, 10(6), 1387; https://doi.org/10.3390/cells10061387 - 4 Jun 2021

Cited by 8 | Viewed by 3833

Abstract

PARP2 is a DNA repair protein. The deletion of PARP2 induces mitochondrial biogenesis and mitochondrial activity by increasing NAD⁺ levels and inducing SIRT1 activity. We show that the silencing of PARP2 causes mitochondrial fragmentation in myoblasts. We assessed multiple pathways that can [...] Read more.

PARP2 is a DNA repair protein. The deletion of PARP2 induces mitochondrial biogenesis and mitochondrial activity by increasing NAD⁺ levels and inducing SIRT1 activity. We show that the silencing of PARP2 causes mitochondrial fragmentation in myoblasts. We assessed multiple pathways that can lead to mitochondrial fragmentation and ruled out the involvement of mitophagy, the fusion–fission machinery, SIRT1, and mitochondrial unfolded protein response. Nevertheless, mitochondrial fragmentation was reversed by treatment with strong reductants, such as reduced glutathione (GSH), N-acetyl-cysteine (NAC), and a mitochondria-specific antioxidant MitoTEMPO. The effect of MitoTEMPO on mitochondrial morphology indicates the production of reactive oxygen species of mitochondrial origin. Elimination of reactive oxygen species reversed mitochondrial fragmentation in PARP2-silenced cells. Full article

(This article belongs to the Special Issue Molecular Role of PARP in Health and Disease 2020)

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11 pages, 2062 KiB

Open AccessFeature PaperArticle

New Insights into the Significance of PARP-1 Activation: Flow Cytometric Detection of Poly(ADP-Ribose) as a Marker of Bovine Intramammary Infection

by Giovanna De Matteis, Francesco Grandoni, Michele Zampieri, Anna Reale and Maria Carmela Scatà

Cells 2021, 10(3), 599; https://doi.org/10.3390/cells10030599 - 9 Mar 2021

Cited by 2 | Viewed by 2775

Abstract

Bovine intramammary infections are common diseases affecting dairy cattle worldwide and represent a major focus of veterinary research due to financial losses and food safety concerns. The identification of new biomarkers of intramammary infection, useful for monitoring the health of dairy cows and [...] Read more.

Bovine intramammary infections are common diseases affecting dairy cattle worldwide and represent a major focus of veterinary research due to financial losses and food safety concerns. The identification of new biomarkers of intramammary infection, useful for monitoring the health of dairy cows and wellness verification, represents a key advancement having potential beneficial effects on public health. In vitro experiments using bovine peripheral blood mononuclear cells (PBMC), stimulated with the bacterial endotoxin lipopolysaccharide (LPS) enabled a flow cytometric assay in order to evaluate in vivo poly-ADP-ribose (PAR) levels. Results showed a significant increase of PAR after 1 h of treatment, which is consistent with the involvement of PARP activity in the inflammatory response. This study investigated PARP-1 activation in leukocyte subpopulations from bovine milk samples during udder infection. A flow cytometric assay was, therefore, performed to evaluate the PAR content in milk leukocyte subsets of cows with and without intramammary infection (IMI). Results showed that milk lymphocytes and macrophages isolated from cows with IMI had a significant increase of PAR content compared to uninfected samples. These results suggest mastitis as a new model for the study of the role of PARP in zoonotic inflammatory diseases, opening a new perspective to the “One Health” approach. Full article

(This article belongs to the Special Issue Molecular Role of PARP in Health and Disease 2020)

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21 pages, 2467 KiB

Open AccessArticle

PARP1 as a Marker of an Aggressive Clinical Phenotype in Cutaneous Melanoma—A Clinical and an In Vitro Study

by Piotr Kupczyk, Aleksandra Simiczyjew, Jakub Marczuk, Ewelina Dratkiewicz, Artur Beberok, Jakub Rok, Malgorzata Pieniazek, Przemyslaw Biecek, Dmitry Nevozhay, Bartosz Slowikowski, Grzegorz Chodaczek, Dorota Wrzesniok, Dorota Nowak and Piotr Donizy

Cells 2021, 10(2), 286; https://doi.org/10.3390/cells10020286 - 31 Jan 2021

Cited by 13 | Viewed by 3601

Abstract

(1) Background: Poly(ADP-ribose) polymerase 1) (PARP1) is a pleiotropic enzyme involved in several cellular processes, e.g., DNA damage repair, regulation of mitosis, and immune response. Little is known about the role of PARP1 in melanoma development and progression. We aimed to investigate the [...] Read more.

(1) Background: Poly(ADP-ribose) polymerase 1) (PARP1) is a pleiotropic enzyme involved in several cellular processes, e.g., DNA damage repair, regulation of mitosis, and immune response. Little is known about the role of PARP1 in melanoma development and progression. We aimed to investigate the prognostic significance of PARP1 expression in cutaneous melanoma through evaluation of mRNA and protein levels of PARP1 in normal melanocytes and melanoma cell lines, as well as in patients’ tissue material from surgical resections. (2) Methods: An in vitro model was based on two types of normal human melanocytes (HEMn-DP and HEMn-LP) and four melanoma cell lines (A375, WM1341D, Hs294T, and WM9). PARP1 mRNA gene expression was estimated using real-time polymerase chain reaction (RT-PCR), whereas the protein level of PARP1 was evaluated by fluorescence confocal microscopy and then confirmed by Western Blotting analysis. The expression of PARP1 was also assessed by immunohistochemistry in formalin-fixed paraffin-embedded tissues of 128 primary cutaneous melanoma patients and correlated with follow-up and clinicopathologic features. (3) Results: The in vitro study showed that melanoma cells exhibited significantly higher PARP1 expression at mRNA and protein levels than normal melanocytes. High PARP1 expression was also associated with the invasiveness of tumor cells. Elevated nuclear PARP1 expression in patients without nodal metastases strongly correlated with significantly shorter disease-free survival (p = 0.0015) and revealed a trend with shorter cancer-specific overall survival (p = 0.05). High PARP1 immunoreactivity in the lymph node-negative group of patients was significantly associated with higher Breslow tumor thickness, presence of ulceration, and a higher mitotic index (p = 0.0016, p = 0.023, and p < 0.001, respectively). In patients with nodal metastases, high PARP1 expression significantly correlated with the presence of microsatellitosis (p = 0.034), but we did not confirm the prognostic significance of PARP1 expression in these patients. In the entire analyzed group of patients (with and without nodal metastases at the time of diagnosis), PARP1 expression was associated with a high mitotic index (p = 0.001) and the presence of ulceration (p = 0.036). Moreover, in patients with elevated PARP1 expression, melanoma was more frequently located in the skin of the head and neck region (p = 0.015). In multivariate analysis, high PARP1 expression was an independent unfavorable prognosticator in lymph node-negative cutaneous melanoma patients. (4) Conclusions: In vitro molecular biology approaches demonstrated enhanced PARP1 expression in cutaneous melanoma. These results were confirmed by the immunohistochemical study with clinical parameter analysis, which showed that a high level of PARP1 correlated with unfavorable clinical outcome. These observations raise the potential role of PARP1 inhibitor-based therapy in cutaneous melanoma. Full article

(This article belongs to the Special Issue Molecular Role of PARP in Health and Disease 2020)

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12 pages, 4486 KiB

Open AccessArticle

The Prognostic Values of PARP-1 Expression in Uveal Melanoma

by Malgorzata Gajdzis, Stamatios Theocharis, Jerzy Klijanienko, Nathalie Cassoux, Sophie Gardrat, Piotr Donizy, Radoslaw Kaczmarek and Pawel Gajdzis

Cells 2021, 10(2), 285; https://doi.org/10.3390/cells10020285 - 31 Jan 2021

Cited by 9 | Viewed by 2286

Abstract

Background: Uveal melanoma is the most common primary intraocular malignancy in adults. In advanced cases, the prognosis is very poor. Thus far, no effective methods of pharmacotherapy of this cancer have been found. The aim of the study was to evaluate the expression [...] Read more.

Background: Uveal melanoma is the most common primary intraocular malignancy in adults. In advanced cases, the prognosis is very poor. Thus far, no effective methods of pharmacotherapy of this cancer have been found. The aim of the study was to evaluate the expression of PARP-1, the best-known member of the family of poly(ADP-ribose) polymerases, in uveal melanoma and its associations with clinicopathological parameters, overall survival, and disease-free survival. Methods: The study included 91 patients who underwent enucleation due to uveal melanoma. PARP-1 expression was assessed by immunohistochemistry. Results: High PARP-1 expression was associated with more frequent chromosome 3 loss, higher histopathological grade, bigger tumor size, and absence of intrascleral extension. High PARP-1 expression was associated with shorter overall survival time and disease-free survival time. Conclusions: The above findings indicate that high expression of PARP-1 can be considered as an unfavorable prognostic factor in uveal melanoma. Full article

(This article belongs to the Special Issue Molecular Role of PARP in Health and Disease 2020)

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20 pages, 4217 KiB

Open AccessArticle

The PARP Inhibitor Olaparib Modulates the Transcriptional Regulatory Networks of Long Non-Coding RNAs during Vasculogenic Mimicry

by Mónica Fernández-Cortés, Eduardo Andrés-León and Francisco Javier Oliver

Cells 2020, 9(12), 2690; https://doi.org/10.3390/cells9122690 - 15 Dec 2020

Cited by 7 | Viewed by 2930

Abstract

In highly metastatic tumors, vasculogenic mimicry (VM) involves the acquisition by tumor cells of endothelial-like traits. Poly-(ADP-ribose) polymerase (PARP) inhibitors are currently used against tumors displaying BRCA1/2-dependent deficient homologous recombination, and they may have antimetastatic activity. Long non-coding RNAs (lncRNAs) are emerging as [...] Read more.

In highly metastatic tumors, vasculogenic mimicry (VM) involves the acquisition by tumor cells of endothelial-like traits. Poly-(ADP-ribose) polymerase (PARP) inhibitors are currently used against tumors displaying BRCA1/2-dependent deficient homologous recombination, and they may have antimetastatic activity. Long non-coding RNAs (lncRNAs) are emerging as key species-specific regulators of cellular and disease processes. To evaluate the impact of olaparib treatment in the context of non-coding RNA, we have analyzed the expression of lncRNA after performing unbiased whole-transcriptome profiling of human uveal melanoma cells cultured to form VM. RNAseq revealed that the non-coding transcriptomic landscape differed between olaparib-treated and non-treated cells: olaparib significantly modulated the expression of 20 lncRNAs, 11 lncRNAs being upregulated, and 9 downregulated. We subjected the data to different bioinformatics tools and analysis in public databases. We found that copy-number variation alterations in some olaparib-modulated lncRNAs had a statistically significant correlation with alterations in some key tumor suppressor genes. Furthermore, the lncRNAs that were modulated by olaparib appeared to be regulated by common transcription factors: ETS1 had high-score binding sites in the promoters of all olaparib upregulated lncRNAs, while MZF1, RHOXF1 and NR2C2 had high-score binding sites in the promoters of all olaparib downregulated lncRNAs. Finally, we predicted that olaparib-modulated lncRNAs could further regulate several transcription factors and their subsequent target genes in melanoma, suggesting that olaparib may trigger a major shift in gene expression mediated by the regulation lncRNA. Globally, olaparib changed the lncRNA expression landscape during VM affecting angiogenesis-related genes. Full article

(This article belongs to the Special Issue Molecular Role of PARP in Health and Disease 2020)

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12 pages, 3084 KiB

Open AccessArticle

Up-Regulation of PARP1 Expression Significantly Correlated with Poor Survival in Mucosal Melanomas

by Piotr Donizy, Cheng-Lin Wu, Jason Mull, Masakazu Fujimoto, Agata Chłopik, Yan Peng, Sara C. Shalin, M. Angelica Selim, Susana Puig, Maria-Teresa Fernandez-Figueras, Christopher R. Shea, Wojciech Biernat, Janusz Ryś, Andrzej Marszalek and Mai P. Hoang

Cells 2020, 9(5), 1135; https://doi.org/10.3390/cells9051135 - 5 May 2020

Cited by 24 | Viewed by 4377

Abstract

Introduction: Mucosal melanoma is rare and associated with poorer prognosis in comparison to conventional melanoma subtypes. Little is known about the prognostic significance as well as possible associations between PARP1 and immunologic response in mucosal melanoma. Methods: PARP1, PD-L1 and IDO1 immunostains were [...] Read more.

Introduction: Mucosal melanoma is rare and associated with poorer prognosis in comparison to conventional melanoma subtypes. Little is known about the prognostic significance as well as possible associations between PARP1 and immunologic response in mucosal melanoma. Methods: PARP1, PD-L1 and IDO1 immunostains were performed on 192 mucosal melanomas including 86 vulvar, 89 sinonasal, and 17 anorectal melanomas. Results: By Kaplan–Meier analyses, high PARP1 expression correlated with worse overall and melanoma-specific survival (log-rank p values = 0.026 and 0.047, respectively). Tumors with combined PARP1 and IDO1 high expression correlated with worse overall and melanoma-specific survival (p = 0.015, 0.0034 respectively). By multivariate analyses, high PARP1 expression remained a predictor of worse survival independent of stage. By Fisher’s exact test, high PARP1 expression correlated with highly mitogenic tumors (p = 0.02). High tumoral PD-L1 and IDO1 expression were associated with ulcerated primary tumors (p = 0.019, 0.0019, respectively). By linear regression analyses, correlations between PARP1 expression versus IDO1 expression (p = 0.0001) and mitotic index (p = 0.0052) were observed. Conclusion: Increased expression of PARP1 is an independent negative prognostic marker in mucosal melanomas. The association between PARP1 and IDO1 and their combined adverse prognostic role raise the potential of combined therapy in mucosal melanoma. Full article

(This article belongs to the Special Issue Molecular Role of PARP in Health and Disease 2020)

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Review

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33 pages, 1288 KiB

Open AccessReview

The Role of PARP1 in Monocyte and Macrophage Commitment and Specification: Future Perspectives and Limitations for the Treatment of Monocyte and Macrophage Relevant Diseases with PARP Inhibitors

by Maciej Sobczak, Marharyta Zyma and Agnieszka Robaszkiewicz

Cells 2020, 9(9), 2040; https://doi.org/10.3390/cells9092040 - 6 Sep 2020

Cited by 17 | Viewed by 5589

Abstract

Modulation of PARP1 expression, changes in its enzymatic activity, post-translational modifications, and inflammasome-dependent cleavage play an important role in the development of monocytes and numerous subtypes of highly specialized macrophages. Transcription of PARP1 is governed by the proliferation status of cells at each [...] Read more.

Modulation of PARP1 expression, changes in its enzymatic activity, post-translational modifications, and inflammasome-dependent cleavage play an important role in the development of monocytes and numerous subtypes of highly specialized macrophages. Transcription of PARP1 is governed by the proliferation status of cells at each step of their development. Higher abundance of PARP1 in embryonic stem cells and in hematopoietic precursors supports their self-renewal and pluri-/multipotency, whereas a low level of the enzyme in monocytes determines the pattern of surface receptors and signal transducers that are functionally linked to the NFκB pathway. In macrophages, the involvement of PARP1 in regulation of transcription, signaling, inflammasome activity, metabolism, and redox balance supports macrophage polarization towards the pro-inflammatory phenotype (M1), which drives host defense against pathogens. On the other hand, it seems to limit the development of a variety of subsets of anti-inflammatory myeloid effectors (M2), which help to remove tissue debris and achieve healing. PARP inhibitors, which prevent protein ADP-ribosylation, and PARP1‒DNA traps, which capture the enzyme on chromatin, may allow us to modulate immune responses and the development of particular cell types. They can be also effective in the treatment of monocytic leukemia and other cancers by reverting the anti- to the proinflammatory phenotype in tumor-associated macrophages. Full article

(This article belongs to the Special Issue Molecular Role of PARP in Health and Disease 2020)

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15 pages, 1873 KiB

Open AccessFeature PaperReview

Emerging Roles of Post-Translational Modifications in Nucleotide Excision Repair

by Barbara N. Borsos, Hajnalka Majoros and Tibor Pankotai

Cells 2020, 9(6), 1466; https://doi.org/10.3390/cells9061466 - 15 Jun 2020

Cited by 11 | Viewed by 4405

Abstract

Nucleotide excision repair (NER) is a versatile DNA repair pathway which can be activated in response to a broad spectrum of UV-induced DNA damage, such as bulky adducts, including cyclobutane-pyrimidine dimers (CPDs) and 6–4 photoproducts (6–4PPs). Based on the genomic position of the [...] Read more.

Nucleotide excision repair (NER) is a versatile DNA repair pathway which can be activated in response to a broad spectrum of UV-induced DNA damage, such as bulky adducts, including cyclobutane-pyrimidine dimers (CPDs) and 6–4 photoproducts (6–4PPs). Based on the genomic position of the lesion, two sub-pathways can be defined: (I) global genomic NER (GG-NER), involved in the ablation of damage throughout the whole genome regardless of the transcription activity of the damaged DNA locus, and (II) transcription-coupled NER (TC-NER), activated at DNA regions where RNAPII-mediated transcription takes place. These processes are tightly regulated by coordinated mechanisms, including post-translational modifications (PTMs). The fine-tuning modulation of the balance between the proteins, responsible for PTMs, is essential to maintain genome integrity and to prevent tumorigenesis. In this review, apart from the other substantial PTMs (SUMOylation, PARylation) related to NER, we principally focus on reversible ubiquitylation, which involves E3 ubiquitin ligase and deubiquitylase (DUB) enzymes responsible for the spatiotemporally precise regulation of NER. Full article

(This article belongs to the Special Issue Molecular Role of PARP in Health and Disease 2020)

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