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poly ADP-ribose polymerase

Ryan A Rogge, Bryan A Gibson, W Lee Kraus
Nuclear poly(ADP-ribose) polymerases (PARPs), including PARPs 1, 2, and 3 and the Tankyrases, belong to a family of enzymes that can bind to chromatin and covalently modify histone- and chromatin-associated proteins with ADP-ribose derived from nuclear NAD+ . The genomic loci where the nuclear PARPs bind and covalently modify chromatin are a fundamental question in PARP biology. Chromatin immunoprecipitation coupled with deep sequencing (ChIP-seq) has become an essential tool for determining specific sites of binding and modification genome-wide...
2018: Methods in Molecular Biology
Florian J Bock, Paul Chang
Posttranscriptional regulation of RNA is an important component of gene expression by controlling the total amount of mRNA available for translation into protein. It involves multiple pathways including nuclear processing of mRNA and its precursors, RNA silencing, and regulation of RNA decay. Poly(ADP-ribose) polymerases (PARPs), enzymes that modify target proteins with ADP-ribose, play important roles in several RNA-regulatory pathways. RNA-binding PARPs target specific transcripts for regulation, and multiple PARPs ADP-ribosylate RNA-regulatory proteins to alter their localization, activity, or RNA binding...
2018: Methods in Molecular Biology
Ilsa T Kirby, Rory K Morgan, Michael S Cohen
Poly-ADP-ribose polymerases (also known as ADP-ribosyltransferases or ARTDs) are a family of 17 enzymes in humans that catalyze the reversible posttranslational modification known as ADP-ribosylation. PARPs are implicated in diverse cellular processes, from DNA repair to the unfolded protein response. Small-molecule inhibitors of PARPs have improved our understanding of PARP-mediated biology and, in some cases, have emerged as promising treatments for cancers and other human diseases. However these advancements are hindered, in part, by a poor understanding of inhibitor selectivity across the PARP family...
2018: Methods in Molecular Biology
Masato Mashimo, Joel Moss
The ARH family of ADP-ribosyl-acceptor hydrolases is composed of three 39-kDa proteins (ARH1, 2, and 3), which hydrolyze specific ADP-ribosylated substrates. ARH1 hydrolyzes mono(ADP-ribosyl)ated arginine, which results from actions of cholera toxin and other nicotinamide adenine dinucleotide (NAD+ ):arginine ADP-ribosyl-transferases, while ARH3 hydrolyzes poly(ADP-ribose) and O-acetyl-ADP-ribose, resulting from the action of poly(ADP-ribose) polymerases and sirtuins, respectively. ARH2 has not been reported to have enzymatic activity, because of differences in the catalytic domain...
2018: Methods in Molecular Biology
Anna-Lena Kolb, Duen-Wei Hsu, Ana B A Wallis, Seiji Ura, Alina Rakhimova, Catherine J Pears, Nicholas D Lakin
The amoeba Dictyostelium discoideum is a single-cell organism that can undergo a simple developmental program, making it an excellent model to study the molecular mechanisms of cell motility, signal transduction, and cell-type differentiation. A variety of human genes that are absent or show limited conservation in other invertebrate models have been identified in this organism. This includes ADP-ribosyltransferases, also known as poly-ADP-ribose polymerases (PARPs), a family of proteins that catalyze the addition of single or poly-ADP-ribose moieties onto target proteins...
2018: Methods in Molecular Biology
David Hutin, Giulia Grimaldi, Jason Matthews
TCDD-inducible poly-ADP-ribose polymerase (TIPARP; also known as PARP7 and ARTD14) is a mono-ADP-ribosyltransferase that has emerged as an important regulator of innate immunity, stem cell pluripotency, and transcription factor regulation. Characterizing TIPARP's catalytic activity and identifying its target proteins are critical to understanding its cellular function. Here we describe methods that we use to characterize TIPARP catalytic activity and its mono-ADP-ribosylation of its target proteins.
2018: Methods in Molecular Biology
Ken Y Lin, Dan Huang, W Lee Kraus
ADP-ribosylation is a covalent posttranslational modification of proteins that is catalyzed by various types of ADP-ribosyltransferase (ART) enzymes, including members of the poly(ADP-ribose) polymerase (PARP) family. ADP-ribose (ADPR) modifications can occur as mono(ADP-ribosyl)ation, oligo(ADP-ribosyl)ation, or poly(ADP-ribosyl)ation, depending on the particular ART enzyme catalyzing the reaction, as well as the specific reaction conditions. Understanding the biology of ADP-ribosylation requires facile and robust means of generating and detecting the modification in all of its forms...
2018: Methods in Molecular Biology
Zhizhi Wang, Wenqing Xu
The poly(ADP-ribose) polymerase (PARP) family of proteins utilize NAD+ as the substrate to modify protein acceptors with either mono(ADP-ribose) (MAR) or poly(ADP-ribose) (PAR). MAR and PAR have been shown to regulate distinct cellular processes. Iso-ADP-ribose (iso-ADPr) is the smallest internal PAR structural unit containing the characteristic ribose-ribose glycosidic bond formed during poly(ADP-ribosyl)ation. The WWE domain of RNF146 specifically recognizes the iso-ADPr moiety in PAR but does not interact with MAR...
2018: Methods in Molecular Biology
Ho Jeong Lee, Venu Venkatarame Gowda Saralamma, Seong Min Kim, Sang Eun Ha, Suchismita Raha, Won Sup Lee, Eun Hee Kim, Sang Joon Lee, Jeong Doo Heo, Gon Sup Kim
Pectolinarigenin (PEC), a natural flavonoid present in Cirsium chanroenicum and in some species of Citrus fruits, has various pharmacological benefits such as anti-inflammatory and anti-cancer activities. In the present study, we investigated the anti-cancer mechanism of PEC induced cell death caused by autophagy and apoptosis in AGS and MKN28 human gastric cancer cells. The PEC treatment significantly inhibited the AGS and MKN28 cell growth in a dose-dependent manner. Further, PEC significantly elevated sub-G1 phase in AGS cells and G2/M phase cell cycle arrest in both AGS and MKN28 cells...
August 8, 2018: Nutrients
Longtai You, Xiaoxv Dong, Boran Ni, Jing Fu, Chunjing Yang, Xingbin Yin, Xin Leng, Jian Ni
Triptolide isolated from the traditional Chinese herb Tripterygium wilfordii Hook F., possesses anti-tumor, anti-fertility, and anti-inflammatory properties. Triptolide-induced hepatotoxicity has continued to engage the attention of researchers. However, not much is yet known about the cytotoxicity of triptolide, and the precise mechanisms involved. In the present study, we investigated the cytotoxicity of triptolide and its underlying mechanisms, using the in vitro model (HepaRG cell). The results demonstrated that triptolide significantly reduced cell viability and induced apoptosis in HepaRG cells in a dose- and time-dependent manner...
2018: Frontiers in Pharmacology
James Stewart, Angela George, Susana Banerjee
Despite treatment strategies which include both surgery and chemotherapy, epithelial ovarian cancer often relapses and survival rates remain poor. There is therefore a need to identify novel treatment targets and develop approaches that improve outcomes. The role of both germ line and somatic mutations in BRCA1 and BRCA2 in the development of ovarian cancer is well established, with mutation in either gene resulting in deficiencies in homologous recombination. Olaparib is an orally active inhibitor of poly(ADP-ribose) polymerase (PARP) which has demonstrated anti-tumour activity in ovarian cancer...
August 9, 2018: Expert Review of Anticancer Therapy
Johannes Rudolph, Jyothi Mahadevan, Pamela Dyer, Karolin Luger
Poly(ADP-ribose) polymerase 1 (PARP1) is both a first responder to DNA damage and a chromatin architectural protein. How PARP1 rapidly finds DNA damage sites in the context of a nucleus filled with undamaged DNA, to which it also binds, is an unresolved question. Here we show that PARP1 association with DNA is diffusion-limited, and release of PARP1 from DNA is promoted by binding of an additional DNA molecule that facilitates a 'monkey bar' mechanism, also known as intersegment transfer. The WGR-domain of PARP1 is essential to this mechanism, and a point mutation (W589A) recapitulates the altered kinetics of the domain deletion...
August 8, 2018: ELife
Sharon D'souza, Veeranjaneyulu Addepalli
Worldwide oral cancer is creating an alarming situation and it's a matter of global concern as it is the 11th most common carcinoma around the globe. After cardiovascular ailments, cancer is the next biggest killer. Approximately 90% of the total oral malignancies are squamous cell carcinomas. The etiological base of oral cancer is tobacco intake, smoking, smokeless tobacco (snuff or chewing tobacco), alcohol and areca nut intake, excessive sunlight exposure, reverse end smoking and Human Papilloma Virus (HPV)...
August 3, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Roisin E O'Cearbhaill
Poly(ADP-ribose) polymerase (PARP) proteins are used by cells in several DNA repair processes. PARP inhibition can result in preferential death of cancer cells when another mechanism for repairing DNA is defective. Two PARP inhibitors, olaparib and rucaparib, have been approved by the US Food and Drug Administration (FDA) for the treatment of recurrent, BRCA-associated ovarian cancer. More recently, these two and a third PARP inhibitor, niraparib, were approved by the FDA as maintenance therapy following platinum-based chemotherapy for recurrent ovarian cancer...
July 15, 2018: Oncology (Williston Park, NY)
Giovanna De Matteis, Anna Reale, Francesco Grandoni, Mirella L Meyer-Ficca, Maria Carmela Scatà, Ralph G Meyer, Luca Buttazzoni, Bianca Moioli
Poly(ADP-ribosyl)ation (PAR) is a post-translational protein modification catalysed by enzyme member of the poly(ADP-ribose) polymerases (PARPs) family. The activation of several PARPs is triggered by DNA strand breakage and the main PARP enzyme involved in this process is PARP1. Besides its involvement in DNA repair, PARP1 is involved in several cellular processes including transcription, epigenetics, chromatin re-modelling as well as in the maintenance of genomic stability. Moreover, several studies in human and animal models showed PARP1 activation in various inflammatory disorders...
August 2018: Veterinary Immunology and Immunopathology
Judit Márton, Mária Péter, Gábor Balogh, Beáta Bódi, Andras Vida, Magdolna Szántó, Dora Bojcsuk, Laura Jankó, Harjit Pal Bhattoa, Imre Gombos, Karen Uray, Ibolya Horváth, Zsolt Török, Balint L Balint, Zoltán Papp, László Vígh, Péter Bai
There is a growing body of evidence that poly(ADP-ribose) polymerase-2 (PARP2), although originally described as a DNA repair protein, has a widespread role as a metabolic regulator. We show that the ablation of PARP2 induced characteristic changes in the lipidome. The silencing of PARP2 induced the expression of sterol regulatory element-binding protein-1 and -2 and initiated de novo cholesterol biosynthesis in skeletal muscle. Increased muscular cholesterol was shunted to muscular biosynthesis of dihydrotestosterone, an anabolic steroid...
August 2, 2018: Biochimica et Biophysica Acta
Jeffrey P Chmielewski, Sarah C Bowlby, Frances B Wheeler, Lihong Shi, Guangchao Sui, Amanda L Davis, Timothy D Howard, Ralph B D'Agostino, Lance D Miller, S Joseph Sirintrapun, Scott D Cramer, Steven J Kridel
Tumor cells require increased rates of cell metabolism to generate the macromolecules necessary to sustain proliferation. They rely heavily on nicotinamide adenine dinucleotide (NAD+) as a cofactor for multiple metabolic enzymes in anabolic and catabolic reactions. NAD+ also serves as a substrate for poly ADP-ribose polymerases (PARPs), sirtuins, and cyclic ADP-ribose synthases. Dysregulation of the cyclic ADP-ribose synthase CD38, the main NAD'ase in cells, is reported in multiple cancer types. This study demonstrates a novel connection between CD38, modulation of NAD+, and tumor cell metabolism in prostate cancer (PCa)...
August 3, 2018: Molecular Cancer Research: MCR
Mohit Thummar, Bhoopendra S Kuswah, Gananadhamu Samanthula, Upendra Bulbake, Jitendra Gour, Wahid Khan
Olaparib (OLA) is a poly ADP ribose polymerase (PARP) enzyme inhibitor used to treat prostate, ovarian and breast cancer. The drug substance OLA was subjected to forced degradation as per ICH prescribed guidelines. It was degraded in hydrolytic (acidic and basic) and oxidative stress conditions and yielded four degradation products (DPs) while it remained stable in neutral hydrolytic, dry heat and photolytic stress conditions. A stability indicating assay method was developed to separate OLA and its DPs using InertSustain C18 column (250 × 4...
July 18, 2018: Journal of Pharmaceutical and Biomedical Analysis
Young-A Heo, Sean T Duggan
Niraparib (Zejula® ), a poly (ADP-ribose) polymerase (PARP) inhibitor, is approved for the maintenance treatment of recurrent, epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who are in complete or partial response to platinum-based chemotherapy. Approval was based on the results of the randomized, double-blind, placebo-controlled phase III NOVA trial. In NOVA, niraparib significantly prolonged progression-free survival (primary endpoint), chemotherapy-free interval and time to first subsequent therapy compared with placebo in patients with recurrent, platinum-sensitive, high grade serous ovarian, fallopian tube or primary peritoneal cancer...
August 3, 2018: Targeted Oncology
Daniela Femia, Natalie Prinzi, Andrea Anichini, Roberta Mortarini, Federico Nichetti, Francesca Corti, Martina Torchio, Giorgia Peverelli, Filippo Pagani, Andrea Maurichi, Ilaria Mattavelli, Massimo Milione, Nice Bedini, Ambra Corti, Maria Di Bartolomeo, Filippo de Braud, Sara Pusceddu
Advanced Merkel cell carcinoma (MCC) is a very aggressive, rare neuroendocrine tumor of the skin with a high frequency of locoregional recurrence and metastasis, and a high mortality rate. Surgical resection, sentinel lymph node biopsy, and radiotherapy represent the gold standard of treatment in patients with localized disease, while chemotherapy has a significant role in the treatment of advanced disease. However, no definitive evidence on the survival impact of radiotherapy in the advanced stages has been provided to date, and response to chemotherapy remains brief in the majority of cases, indicating an urgent need for alternative approaches...
August 2, 2018: Targeted Oncology
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