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Cancers
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PARP Enzymes, ADP-Ribose and NAD+ Metabolism in Cancer
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PARP Enzymes, ADP-Ribose and NAD+ Metabolism in Cancer

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (30 April 2023) | Viewed by 20535

Special Issue Editors

Prof. Dr. Péter Bay

E-Mail Website
Guest Editor
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
Dr. José Yélamos

E-Mail Website
Guest Editor
1. Cancer Research Program, Hospital del Mar Medical Research Institute, 08003 Barcelona, Spain
2. Laboratory of Immunology, Department of Pathology, Hospital del Mar, 08003 Barcelona, Spain
Interests: PARP; DNA damage; tumor cell; immune response
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We are arranging a Special Issue in the journal Cancers (Impact Factor: 6.639). This Special Issue of Cancers will consist of research and review articles on “PARP Enzymes, ADP-ribose, and NAD+ Metabolism in Cancer”. It will focus on selected papers from the FEBS Advanced Lecture Course conference on “PARP2021: Research on the Family of Poly(ADP-ribose) Polymerases” (https://parp2021.febsevents.org/), that takes place in Barcelona (Spain) on 7–10 September 2021, but all manuscripts relevant to the topic are welcome.

PARPs were discovered in the 1960s, with their role in DNA repair and maintenance of DNA structure first being established. The development of PARP inhibitors allowed the identification of a plethora of other PARP-mediated biological processes ranging from metabolism, through viral biology to aging. Establishing knockout mouse strains further widened the scope of our understanding of PARP biology. Novel mass-spectrometry-based methods can establish the PARylome in biological models and can be of help to identify binding partners of PARPs or proteins that bind PAR itself. These findings led to the development of specific PARP inhibitors that are now available in clinical practice.

The aim of this Special Issue is to offer an up-to-date overview of the current developments in the PARP arena and contribute with new original results.

Prof. Dr. Péter Bay
Dr. José Yélamos
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

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Published Papers (5 papers)

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Research

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18 pages, 1960 KiB  
Article
PARP10 Mediates Mono-ADP-Ribosylation of Aurora-A Regulating G2/M Transition of the Cell Cycle
by Simone Di Paola, Maria Matarese, Maria Luisa Barretta, Nina Dathan, Antonino Colanzi, Daniela Corda and Giovanna Grimaldi
Cancers 2022, 14(21), 5210; https://doi.org/10.3390/cancers14215210 - 24 Oct 2022
Cited by 7 | Viewed by 2433
Abstract
Intracellular mono-ADP-ribosyltransferases (mono-ARTs) catalyze the covalent attachment of a single ADP-ribose molecule to protein substrates, thus regulating their functions. PARP10 is a soluble mono-ART involved in the modulation of intracellular signaling, metabolism and apoptosis. PARP10 also participates in the regulation of the G1- [...] Read more.
Intracellular mono-ADP-ribosyltransferases (mono-ARTs) catalyze the covalent attachment of a single ADP-ribose molecule to protein substrates, thus regulating their functions. PARP10 is a soluble mono-ART involved in the modulation of intracellular signaling, metabolism and apoptosis. PARP10 also participates in the regulation of the G1- and S-phase of the cell cycle. However, the role of this enzyme in G2/M progression is not defined. In this study, we found that genetic ablation, protein depletion and pharmacological inhibition of PARP10 cause a delay in the G2/M transition of the cell cycle. Moreover, we found that the mitotic kinase Aurora-A, a previously identified PARP10 substrate, is actively mono-ADP-ribosylated (MARylated) during G2/M transition in a PARP10-dependent manner. Notably, we showed that PARP10-mediated MARylation of Aurora-A enhances the activity of the kinase in vitro. Consistent with an impairment in the endogenous activity of Aurora-A, cells lacking PARP10 show a decreased localization of the kinase on the centrosomes and mitotic spindle during G2/M progression. Taken together, our data provide the first evidence of a direct role played by PARP10 in the progression of G2 and mitosis, an event that is strictly correlated to the endogenous MARylation of Aurora-A, thus proposing a novel mechanism for the modulation of Aurora-A kinase activity. Full article
(This article belongs to the Special Issue PARP Enzymes, ADP-Ribose and NAD+ Metabolism in Cancer)
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20 pages, 3856 KiB  
Article
Live Cell Detection of Poly(ADP-Ribose) for Use in Genetic and Genotoxic Compound Screens
by Christopher A. Koczor, Aaron J. Haider, Kate M. Saville, Jianfeng Li, Joel F. Andrews, Alison V. Beiser and Robert W. Sobol
Cancers 2022, 14(15), 3676; https://doi.org/10.3390/cancers14153676 - 28 Jul 2022
Cited by 5 | Viewed by 2877
Abstract
Poly(ADP-ribose) (PAR) is a molecular scaffold that aids in the formation of DNA repair protein complexes. Tools to sensitively quantify PAR in live cells have been lacking. We recently described the LivePAR probe (EGFP fused to the RNF146-encoded WWE PAR binding domain) to [...] Read more.
Poly(ADP-ribose) (PAR) is a molecular scaffold that aids in the formation of DNA repair protein complexes. Tools to sensitively quantify PAR in live cells have been lacking. We recently described the LivePAR probe (EGFP fused to the RNF146-encoded WWE PAR binding domain) to measure PAR formation at sites of laser micro-irradiation in live cells. Here, we present two methods that expand on the use of LivePAR and its WWE domain. First, LivePAR enriches in the nucleus of cells following genotoxic challenge. Image quantitation can identify single-cell PAR formation following genotoxic stress at concentrations lower than PAR ELISA or PAR immunoblot, with greater sensitivity to genotoxic stress than CometChip. In a second approach, we used the RNF146-encoded WWE domain to develop a split luciferase probe for analysis in a 96-well plate assay. We then applied these PAR analysis tools to demonstrate their broad applicability. First, we show that both approaches can identify genetic modifications that alter PARylation levels, such as hyper-PARylation in BRCA2-deficient cancer cells. Second, we demonstrate the utility of the WWE split luciferase assay to characterize the cellular response of genotoxins, PARP inhibitors, and PARG inhibitors, thereby providing a screening method to identify PAR modulating compounds. Full article
(This article belongs to the Special Issue PARP Enzymes, ADP-Ribose and NAD+ Metabolism in Cancer)
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20 pages, 2638 KiB  
Article
Attenuation of Muscle Damage, Structural Abnormalities, and Physical Activity in Respiratory and Limb Muscles following Treatment with Rucaparib in Lung Cancer Cachexia Mice
by Maria Pérez-Peiró, Xavier Duran, José Yélamos and Esther Barreiro
Cancers 2022, 14(12), 2894; https://doi.org/10.3390/cancers14122894 - 11 Jun 2022
Cited by 2 | Viewed by 2417
Abstract
Overactivation of poly (ADPribose) polymerases (PARPs) is involved in cancer-induced cachexia. We hypothesized that the PARP inhibitor rucaparib may improve muscle mass and reduce damage in cancer cachexia mice. In mouse diaphragm and gastrocnemius (LP07 lung adenocarcinoma) treated with PARP inhibitor (rucaparib,150 mg/kg [...] Read more.
Overactivation of poly (ADPribose) polymerases (PARPs) is involved in cancer-induced cachexia. We hypothesized that the PARP inhibitor rucaparib may improve muscle mass and reduce damage in cancer cachexia mice. In mouse diaphragm and gastrocnemius (LP07 lung adenocarcinoma) treated with PARP inhibitor (rucaparib,150 mg/kg body weight/24 h for 20 days) and in non-tumor control animals, body, muscle, and tumor weights; tumor area; limb muscle strength; physical activity; muscle structural abnormalities, damage, and phenotype; PARP activity; and proteolytic and autophagy markers were quantified. In cancer cachexia mice compared to non-cachexia controls, body weight and body weight gain, muscle weight, limb strength, physical activity, and muscle fiber size significantly declined, while levels of PARP activity, plasma troponin I, muscle damage, and proteolytic and autophagy markers increased. Treatment with the PARP inhibitor rucaparib elicited a significant improvement in body weight gain, tumor size and weight, physical activity, muscle damage, troponin I, and proteolytic and autophagy levels. PARP pharmacological inhibition did not exert any significant improvements in muscle weight, fiber size, or limb muscle strength. Treatment with rucaparib, however, improved muscle damage and structural abnormalities and physical activity in cancer cachexia mice. These findings suggest that rucaparib exerts its beneficial effects on cancer cachexia performance through the restoration of muscle structure. Full article
(This article belongs to the Special Issue PARP Enzymes, ADP-Ribose and NAD+ Metabolism in Cancer)
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Review

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23 pages, 2208 KiB  
Review
Targeting Homologous Recombination Deficiency in Ovarian Cancer with PARP Inhibitors: Synthetic Lethal Strategies That Impact Overall Survival
by Tao Xie, Kristie-Ann Dickson, Christine Yee, Yue Ma, Caroline E. Ford, Nikola A. Bowden and Deborah J. Marsh
Cancers 2022, 14(19), 4621; https://doi.org/10.3390/cancers14194621 - 23 Sep 2022
Cited by 5 | Viewed by 5028
Abstract
The advent of molecular targeted therapies has made a significant impact on survival of women with ovarian cancer who have defects in homologous recombination repair (HRR). High-grade serous ovarian cancer (HGSOC) is the most common histological subtype of ovarian cancer, with over 50% [...] Read more.
The advent of molecular targeted therapies has made a significant impact on survival of women with ovarian cancer who have defects in homologous recombination repair (HRR). High-grade serous ovarian cancer (HGSOC) is the most common histological subtype of ovarian cancer, with over 50% displaying defective HRR. Poly ADP ribose polymerases (PARPs) are a family of enzymes that catalyse the transfer of ADP-ribose to target proteins, functioning in fundamental cellular processes including transcription, chromatin remodelling and DNA repair. In cells with deficient HRR, PARP inhibitors (PARPis) cause synthetic lethality leading to cell death. Despite the major advances that PARPis have heralded for women with ovarian cancer, questions and challenges remain, including: can the benefits of PARPis be brought to a wider range of women with ovarian cancer; can other drugs in clinical use function in a similar way or with greater efficacy than currently clinically approved PARPis; what can we learn from long-term responders to PARPis; can PARPis sensitise ovarian cancer cells to immunotherapy; and can synthetic lethal strategies be employed more broadly to develop new therapies for women with ovarian cancer. We examine these, and other, questions with focus on improving outcomes for women with ovarian cancer. Full article
(This article belongs to the Special Issue PARP Enzymes, ADP-Ribose and NAD+ Metabolism in Cancer)
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16 pages, 924 KiB  
Review
PARP1: Liaison of Chromatin Remodeling and Transcription
by Wen Zong, Yamin Gong, Wenli Sun, Tangliang Li and Zhao-Qi Wang
Cancers 2022, 14(17), 4162; https://doi.org/10.3390/cancers14174162 - 27 Aug 2022
Cited by 37 | Viewed by 6720
Abstract
Poly(ADP-ribosyl)ation (PARylation) is a covalent post-translational modification and plays a key role in the immediate response of cells to stress signals. Poly(ADP-ribose) polymerase 1 (PARP1), the founding member of the PARP superfamily, synthesizes long and branched polymers of ADP-ribose (PAR) onto acceptor proteins, [...] Read more.
Poly(ADP-ribosyl)ation (PARylation) is a covalent post-translational modification and plays a key role in the immediate response of cells to stress signals. Poly(ADP-ribose) polymerase 1 (PARP1), the founding member of the PARP superfamily, synthesizes long and branched polymers of ADP-ribose (PAR) onto acceptor proteins, thereby modulating their function and their local surrounding. PARP1 is the most prominent of the PARPs and is responsible for the production of about 90% of PAR in the cell. Therefore, PARP1 and PARylation play a pleotropic role in a wide range of cellular processes, such as DNA repair and genomic stability, cell death, chromatin remodeling, inflammatory response and gene transcription. PARP1 has DNA-binding and catalytic activities that are important for DNA repair, yet also modulate chromatin conformation and gene transcription, which can be independent of DNA damage response. PARP1 and PARylation homeostasis have also been implicated in multiple diseases, including inflammation, stroke, diabetes and cancer. Studies of the molecular action and biological function of PARP1 and PARylation provide a basis for the development of pharmaceutic strategies for clinical applications. This review focuses primarily on the role of PARP1 in the regulation of chromatin remodeling and transcriptional activation. Full article
(This article belongs to the Special Issue PARP Enzymes, ADP-Ribose and NAD+ Metabolism in Cancer)
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