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https://www.readbyqxmd.com/read/28032120/inhibition-of-poly-adp-ribosylation-fails-to-increase-axonal-regeneration-or-improve-functional-recovery-after-adult-mammalian-cns-injury
#1
Xingxing Wang, Yuichi Sekine, Alexandra B Byrne, William B J Cafferty, Marc Hammarlund, Stephen M Strittmatter
After traumatic damage of the brain or spinal cord, many surviving neurons are disconnected, and recovery of function is limited by poor axon regeneration. Recent data have suggested that poly ADP-ribosylation plays a role in limiting axonal regrowth such that inhibition of poly (ADP-ribose) polymerase (PARP) may have therapeutic efficacy for neurological recovery after trauma. Here, we tested systemic administration of the PARP inhibitor, veliparib, and showed effective suppression of PARylation in the mouse CNS...
November 2016: ENeuro
https://www.readbyqxmd.com/read/28013023/metabolic-roles-of-poly-adp-ribose-polymerases
#2
REVIEW
András Vida, Judit Márton, Edit Mikó, Péter Bai
Poly(ADP-ribosyl)ation (PARylation) is an evolutionarily conserved reaction that had been associated with numerous cellular processes such as DNA repair, protein turnover, inflammatory regulation, aging or metabolic regulation. The metabolic regulatory tasks of poly(ADP-ribose) polymerases (PARPs) are complex, it is based on the regulation of metabolic transcription factors (e.g. SIRT1, nuclear receptors, SREBPs) and certain cellular energy sensors. PARP over-activation can cause damage to mitochondrial terminal oxidation, while the inhibition of PARP-1 or PARP-2 can induce mitochondrial oxidation by enhancing the mitotropic tone of gene transcription and signal transduction...
December 21, 2016: Seminars in Cell & Developmental Biology
https://www.readbyqxmd.com/read/27965086/the-effect-of-poly-adp-ribosyl-ation-inhibition-on-the-porcine-cumulus-oocyte-complex-during-in%C3%A2-vitro-maturation
#3
Duk Hyoun Kim, Hye Ran Lee, Min Gyeong Kim, Jun Sung Lee, Su Jin Jin, Hoon Taek Lee
Poly(ADP-ribosyl)ation (PARylation) plays important roles in DNA repair, apoptosis, transcriptional regulation, and cell death, and occurs via the activity of poly(ADP-ribose) polymerases (PARPs). Previous studies have shown that PARylation affects mouse and porcine pre-implantation development and participates in mechanisms of autophagy. However, there have not yet been reported the role of PARylation during in vitro maturation (IVM) of porcine oocytes. Thus, we investigated the effect of PARylation inhibition on this process; cumulus-oocyte complexes (COCs) were cultured with 3-aminobenzamide (3-ABA, PARP inhibitor) during porcine IVM...
December 10, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27920426/crystal-structure-based-discovery-of-a-novel-synthesized-parp1-inhibitor-ol-1-with-apoptosis-inducing-mechanisms-in-triple-negative-breast-cancer
#4
Leilei Fu, Shuya Wang, Xuan Wang, Peiqi Wang, Yaxin Zheng, Dahong Yao, Mingrui Guo, Lan Zhang, Liang Ouyang
Poly (ADP-ribose) polymerase-1 (PARP1) is a highly conserved enzyme focused on the self-repair of cellular DNA damage. Until now, numbers of PARP inhibitors have been reported and used for breast cancer therapy in recent years, especially in TNBC. However, developing a new type PARP inhibitor with distinctive skeleton is alternatively promising strategy for TNBC therapy. In this study, based on co-crystallization studies and pharmacophore-docking-based virtual screening, we discovered a series of dihydrodibenzo[b,e]-oxepin compounds as PARP1 inhibitors...
December 2016: Scientific Reports
https://www.readbyqxmd.com/read/27908606/parp1-orchestrates-epigenetic-events-setting-up-chromatin-domains
#5
REVIEW
Fabio Ciccarone, Michele Zampieri, Paola Caiafa
Epigenetic events include reversible modifications of DNA and histone tails driving chromatin organization and thus transcription. The epigenetic regulation is a highly integrated process underlying the plasticity of the genomic information both in the context of complex physiological and pathological processes. The global regulatory aspects of epigenetic events are largely unknown. PARylation and PARP1 are recently emerging as multi-level regulatory effectors that modulate the topology of chromatin by orchestrating very different processes...
November 28, 2016: Seminars in Cell & Developmental Biology
https://www.readbyqxmd.com/read/27817742/parg-inhibitors-and-functional-parg-inhibition-models
#6
Yuka Sasaki, Miyuki Hozumi, Hiroaki Fujimori, Yasufumi Murakami, Fumiaki Koizumi, Kengo Inoue, Mitsuko Masutani
Poly(ADP-ribose) polymerases (PARPs) family proteins catalyze poly(ADP-ribosylation) (PARylation) by conjugating ADP-ribose residues repeatedly on amino acid residues using nicotinamide adenine dinucleotide as a substrate. The inhibitors of PARP widely block DNA repair processes and are currently examined in clinical trials of cancer therapy. Poly(ADP-ribose) glycohydrolase (PARG) is the main nuclear enzyme, which digests poly(ADP-ribose) into ADP-ribose. PARG inhibitor could also be considered as a chemotherapeutic agent for cancer, because of its involvement in DNA repair...
2016: Current Protein & Peptide Science
https://www.readbyqxmd.com/read/27813108/antagonistic-effect-of-n-ethylmaleimide-on-arsenic-mediated-oxidative-stress-induced-poly-adp-ribosyl-ation-and-cytotoxicity
#7
Alexander Sheng-Shin Wang, Yu-Ting Chou, Yeong-Shiau Pu
Long-term exposure to arsenic has been known to induce neoplastic initiation and progression in several organs; however, the role of arsenic (As2 O3 ) in oxidative stress-mediated DNA damage remains elusive. One of the immediate cellular responses to DNA damage is poly(ADP-ribosyl)ation (PARylation), which mediates DNA repair and enhances cell survival. In this study, we found that oxidative stress (H2 O2 )-induced PARylation was suppressed by As2 O3 exposure in different human cancer cells. Moreover, As2 O3 treatment promoted H2 O2 -induced DNA damage and apoptosis, leading to increased cell death...
November 4, 2016: Journal of Applied Toxicology: JAT
https://www.readbyqxmd.com/read/27798264/nad-repletion-improves-muscle-function-in-muscular-dystrophy-and-counters-global-parylation
#8
Dongryeol Ryu, Hongbo Zhang, Eduardo R Ropelle, Vincenzo Sorrentino, Davi A G Mázala, Laurent Mouchiroud, Philip L Marshall, Matthew D Campbell, Amir Safi Ali, Gary M Knowels, Stéphanie Bellemin, Shama R Iyer, Xu Wang, Karim Gariani, Anthony A Sauve, Carles Cantó, Kevin E Conley, Ludivine Walter, Richard M Lovering, Eva R Chin, Bernard J Jasmin, David J Marcinek, Keir J Menzies, Johan Auwerx
Neuromuscular diseases are often caused by inherited mutations that lead to progressive skeletal muscle weakness and degeneration. In diverse populations of normal healthy mice, we observed correlations between the abundance of mRNA transcripts related to mitochondrial biogenesis, the dystrophin-sarcoglycan complex, and nicotinamide adenine dinucleotide (NAD(+)) synthesis, consistent with a potential role for the essential cofactor NAD(+) in protecting muscle from metabolic and structural degeneration. Furthermore, the skeletal muscle transcriptomes of patients with Duchene's muscular dystrophy (DMD) and other muscle diseases were enriched for various poly[adenosine 5'-diphosphate (ADP)-ribose] polymerases (PARPs) and for nicotinamide N-methyltransferase (NNMT), enzymes that are major consumers of NAD(+) and are involved in pleiotropic events, including inflammation...
October 19, 2016: Science Translational Medicine
https://www.readbyqxmd.com/read/27797852/parylation-of-the-forkhead-associated-domain-protein-dawdle-regulates-plant-immunity
#9
Baomin Feng, Shisong Ma, Sixue Chen, Ning Zhu, Shuxin Zhang, Bin Yu, Yu Yu, Brandon Le, Xuemei Chen, Savithramma P Dinesh-Kumar, Libo Shan, Ping He
Protein poly(ADP-ribosyl)ation (PARylation) primarily catalyzed by poly(ADP-ribose) polymerases (PARPs) plays a crucial role in controlling various cellular responses. However, PARylation targets and their functions remain largely elusive. Here, we deployed an Arabidopsis protein microarray coupled with in vitro PARylation assays to globally identify PARylation targets in plants. Consistent with the essential role of PARylation in plant immunity, the forkhead-associated (FHA) domain protein DAWDLE (DDL), one of PARP2 targets, positively regulates plant defense to both adapted and non-adapted pathogens...
December 2016: EMBO Reports
https://www.readbyqxmd.com/read/27793508/dna-maintenance-following-bleomycin-induced-strand-breaks-does-not-require-poly-adp-ribosyl-ation-activation-in-drosophila-s2-cells
#10
Layal Ishak, Amandine Moretton, Isabelle Garreau-Balandier, Mathilde Lefebvre, Serge Alziari, Philippe Lachaume, Frédéric Morel, Géraldine Farge, Patrick Vernet, Pascal Dubessay
BACKGROUND: Poly-ADP ribosylation (PARylation) is a post translational modification, catalyzed by Poly(ADP-ribose)polymerase (PARP) family. In Drosophila, PARP-I (human PARP-1 ortholog) is considered to be the only enzymatically active isoform. PARylation is involved in various cellular processes such as DNA repair in case of base excision and strand-breaks. OBSERVATIONS: Strand-breaks (SSB and DSB) are detrimental to cell viability and, in Drosophila, that has a unique PARP family organization, little is known on PARP involvement in the control of strand-breaks repair process...
October 21, 2016: DNA Repair
https://www.readbyqxmd.com/read/27732836/nad-replenishment-improves-lifespan-and-healthspan-in-ataxia-telangiectasia-models-via-mitophagy-and-dna-repair
#11
Evandro Fei Fang, Henok Kassahun, Deborah L Croteau, Morten Scheibye-Knudsen, Krisztina Marosi, Huiming Lu, Raghavendra A Shamanna, Sumana Kalyanasundaram, Ravi Chand Bollineni, Mark A Wilson, Wendy B Iser, Bradley N Wollman, Marya Morevati, Jun Li, Jesse S Kerr, Qiping Lu, Tyler B Waltz, Jane Tian, David A Sinclair, Mark P Mattson, Hilde Nilsen, Vilhelm A Bohr
Ataxia telangiectasia (A-T) is a rare autosomal recessive disease characterized by progressive neurodegeneration and cerebellar ataxia. A-T is causally linked to defects in ATM, a master regulator of the response to and repair of DNA double-strand breaks. The molecular basis of cerebellar atrophy and neurodegeneration in A-T patients is unclear. Here we report and examine the significance of increased PARylation, low NAD(+), and mitochondrial dysfunction in ATM-deficient neurons, mice, and worms. Treatments that replenish intracellular NAD(+) reduce the severity of A-T neuropathology, normalize neuromuscular function, delay memory loss, and extend lifespan in both animal models...
October 11, 2016: Cell Metabolism
https://www.readbyqxmd.com/read/27725894/understanding-specific-functions-of-parp-2-new-lessons-for-cancer-therapy
#12
REVIEW
Syed O Ali, Farhaan A Khan, Miguel A Galindo-Campos, José Yélamos
Poly(ADP-ribosyl)ation (PARylation) is a widespread and highly conserved post-translational modification catalysed by a large family of enzymes called poly(ADP-ribose) polymerases (PARPs). PARylation plays an essential role in various cardinal processes of cellular physiology and recent approvals and breakthrough therapy designations for PARP inhibitors in cancer therapy have sparked great interest in pharmacological targeting of PARP proteins. Although, many PARP inhibitors have been developed, existing compounds display promiscuous inhibition across the PARP superfamily which could lead to unwanted off-target effects...
2016: American Journal of Cancer Research
https://www.readbyqxmd.com/read/27694308/analyzing-structure-function-relationships-of-artificial-and-cancer-associated-parp1-variants-by-reconstituting-talen-generated-hela-parp1-knock-out-cells
#13
Lisa Rank, Sebastian Veith, Eva C Gwosch, Janine Demgenski, Magdalena Ganz, Marjolijn C Jongmans, Christopher Vogel, Arthur Fischbach, Stefanie Buerger, Jan M F Fischer, Tabea Zubel, Anna Stier, Christina Renner, Michael Schmalz, Sascha Beneke, Marcus Groettrup, Roland P Kuiper, Alexander Bürkle, Elisa Ferrando-May, Aswin Mangerich
Genotoxic stress activates PARP1, resulting in the post-translational modification of proteins with poly(ADP-ribose) (PAR). We genetically deleted PARP1 in one of the most widely used human cell systems, i.e. HeLa cells, via TALEN-mediated gene targeting. After comprehensive characterization of these cells during genotoxic stress, we analyzed structure-function relationships of PARP1 by reconstituting PARP1 KO cells with a series of PARP1 variants. Firstly, we verified that the PARP1\E988K mutant exhibits mono-ADP-ribosylation activity and we demonstrate that the PARP1\L713F mutant is constitutively active in cells...
December 1, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27689873/autophagy-requires-poly-adp-ribosyl-ation-dependent-ampk-nuclear-export
#14
José M Rodríguez-Vargas, María I Rodríguez, Jara Majuelos-Melguizo, Ángel García-Diaz, Ariannys González-Flores, Abelardo López-Rivas, László Virág, Giuditta Illuzzi, Valerie Schreiber, Françoise Dantzer, F Javier Oliver
AMPK is a central energy sensor linking extracellular milieu fluctuations with the autophagic machinery. In the current study we uncover that Poly(ADP-ribosyl)ation (PARylation), a post-translational modification (PTM) of proteins, accounts for the spatial and temporal regulation of autophagy by modulating AMPK subcellular localisation and activation. More particularly, we show that the minority AMPK pool needs to be exported to the cytosol in a PARylation-dependent manner for optimal induction of autophagy, including ULK1 phosphorylation and mTORC1 inactivation...
December 2016: Cell Death and Differentiation
https://www.readbyqxmd.com/read/27686254/the-poly-adp-ribosyl-ation-of-foxo3-mediated-by-parp1-participates-in-isoproterenol-induced-cardiac-hypertrophy
#15
Jing Lu, Renwei Zhang, Huiqi Hong, Zuolong Yang, Duanping Sun, Shuya Sun, Xiaolei Guo, Jiantao Ye, Zhuoming Li, Peiqing Liu
The Forkhead box-containing protein, O subfamily 3 (FoxO3) transcription factor negatively regulates myocardial hypertrophy, and its transcriptional activity is finely conditioned by diverse posttranslational modifications, such as phosphorylation, acetylation, ubiquitination, methylation and glycosylation. Here, we introduce a novel modification of the FoxO3 protein in cardiomyocytes: poly(ADP-ribosyl)ation (PARylation) mediated by poly(ADP-ribose) polymerase-1 (PARP1). This process catalyzes the NAD(+)-dependent synthesis of polymers of ADP-ribose (PAR) and their subsequent attachment to target proteins by PARPs...
December 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27682984/proteomics-insights-into-dna-damage-response-and-translating-this-knowledge-to-clinical-strategies
#16
REVIEW
Louise von Stechow, Jesper V Olsen
Genomic instability is a critical driver in the process of cancer formation. At the same time, inducing DNA damage by irradiation or genotoxic compounds constitutes a key therapeutic strategy to kill fast-dividing cancer cells. Sensing of DNA lesions initiates a complex set of signalling pathways, collectively known as the DNA damage response (DDR). Deciphering DDR signalling pathways with high-throughput technologies could provide insights into oncogenic transformation, metastasis formation and therapy responses, and could build a basis for better therapeutic interventions in cancer treatment...
September 28, 2016: Proteomics
https://www.readbyqxmd.com/read/27670719/expanding-functions-of-adp-ribosylation-in-the-maintenance-of-genome-integrity
#17
K Martin-Hernandez, J-M Rodriguez-Vargas, V Schreiber, F Dantzer
Cell response to genotoxic stress requires a complex network of sensors and effectors from numerous signaling and repair pathways, among them the nuclear poly(ADP-ribose) polymerase 1 (PARP1) plays a central role. PARP1 is catalytically activated in the setting of DNA breaks. It uses NAD(+) as a donor and catalyses the synthesis and subsequent covalent attachment of branched ADP-ribose polymers onto itself and various acceptor proteins to promote repair. Its inhibition is now considered as an efficient therapeutic strategy to potentiate the cytotoxic effect of chemotherapy and radiation or to exploit synthetic lethality in tumours with defective homologous recombination mediated repair...
September 23, 2016: Seminars in Cell & Developmental Biology
https://www.readbyqxmd.com/read/27668604/-poly-adp-ribose-polymerase-1-as-a-key-regulator-of-dna-repair
#18
S N Khodyreva, O I Lavrik
Poly(ADP-ribosyl)ation (PARylation) of proteins is one of the immediate cell responses to DNA damage and is catalyzed by poly(ADP-ribose) polymerases (PARPs). When bound to damaged DNA, some members of the PARP family are activated and use NAD^(+) as a source of ADP to catalyze synthesis of poly(ADP-ribose) (PAR) covalently attached to a target protein. PAR synthesis is considered as a mechanism that provides a local signal of DNA damage and modulates protein functions in response to genotoxic agents. PARP1 is the best-studied protein of the PARP family and is widely known аs a regulator of repair of damaged bases and single-strand nicks...
July 2016: Molekuliarnaia Biologiia
https://www.readbyqxmd.com/read/27667561/small-molecule-chemical-probe-rescues-cells-from-mono-adp-ribosyltransferase-artd10-parp10-induced-apoptosis-and-sensitizes-cancer-cells-to-dna-damage
#19
Harikanth Venkannagari, Patricia Verheugd, Jarkko Koivunen, Teemu Haikarainen, Ezeogo Obaji, Yashwanth Ashok, Mohit Narwal, Taina Pihlajaniemi, Bernhard Lüscher, Lari Lehtiö
Members of the human diphtheria toxin-like ADP-ribosyltransferase (ARTD or PARP) family play important roles in regulating biological activities by mediating either a mono-ADP-ribosylation (MARylation) of a substrate or a poly-ADP-ribosylation (PARylation). ARTD10/PARP10 belongs to the MARylating ARTDs (mARTDs) subfamily, and plays important roles in biological processes that range from cellular signaling, DNA repair, and cell proliferation to immune response. Despite their biological and disease relevance, no selective inhibitors for mARTDs are available...
October 20, 2016: Cell Chemical Biology
https://www.readbyqxmd.com/read/27664469/parping-for-balance-in-the-homeostasis-of-poly-adp-ribosyl-ation
#20
Harald Schuhwerk, Reham Atteya, Kanstantsin Siniuk, Zhao-Qi Wang
Despite more than 50 years of research, the vast majority of the biology of poly(ADP-ribosyl)ation (PARylation) still remains a gross mystery. Originally described to be a part of the DNA repair machinery, poly(ADP-ribose) (PAR) is synthesized immediately by poly(ADP-ribose) polymerases (PARPs, also known as ARTDs) upon DNA damage and then rapidly removed by degrading enzymes. PAR provides a delicate and spatiotemporal interaction scaffold for numerous target proteins. Thus, the multifaceted PARylation system, consisting of PAR itself and its synthesizers and erasers, plays diverse roles in the DNA damage response (DDR), in DNA repair, transcription, replication, chromatin remodelling, metabolism and cell death...
September 21, 2016: Seminars in Cell & Developmental Biology
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