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Débora Broch Trentini, Marcin Józef Suskiewicz, Alexander Heuck, Robert Kurzbauer, Luiza Deszcz, Karl Mechtler, Tim Clausen
Protein turnover is a tightly controlled process critical for the removal of aberrant polypeptides and for cellular signalling. Whereas ubiquitin marks eukaryotic proteins for proteasomal degradation, a general tagging system for the equivalent bacterial Clp proteases is not known. Here we address the targeting mechanism of the ClpC:ClpP proteolytic complex from Bacillus subtilis. Quantitative affinity proteomics using a ClpP trapping mutant show that proteins phosphorylated on arginine residues are selectively targeted to ClpC:ClpP...
October 6, 2016: Nature
Alexandra B Byrne, Rebecca D McWhirter, Yuichi Sekine, Stephen M Strittmatter, David M Miller, Marc Hammarlund
The ability of a neuron to regenerate its axon after injury depends in part on its intrinsic regenerative potential. Here, we identify novel intrinsic regulators of axon regeneration: poly(ADP-ribose) glycohodrolases (PARGs) and poly(ADP-ribose) polymerases (PARPs). PARGs, which remove poly(ADP-ribose) from proteins, act in injured C. elegans GABA motor neurons to enhance axon regeneration. PARG expression is regulated by DLK signaling, and PARGs mediate DLK function in enhancing axon regeneration. Conversely, PARPs, which add poly(ADP-ribose) to proteins, inhibit axon regeneration of both C...
October 4, 2016: ELife
Dominic I James, Kate M Smith, Allan M Jordan, Emma E Fairweather, Louise A Griffiths, Nicola S Hamilton, James R Hitchin, Colin P Hutton, Stuart Jones, Paul Kelly, Alison E McGonagle, Helen Small, Alexandra I J Stowell, Julie Tucker, Ian D Waddell, Bohdan Waszkowycz, Donald J Ogilvie
The enzyme poly(ADP-ribose) glycohydrolase (PARG) performs a critical role in the repair of DNA single strand breaks (SSBs). However, a detailed understanding of its mechanism of action has been hampered by a lack of credible, cell-active chemical probes. Herein, we demonstrate inhibition of PARG with a small molecule, leading to poly(ADP-ribose) (PAR) chain persistence in intact cells. Moreover, we describe two advanced, and chemically distinct, cell-active tool compounds with convincing on-target pharmacology and selectivity...
October 12, 2016: ACS Chemical Biology
Dominic I James, Stephen Durant, Kay Eckersley, Emma Fairweather, Louise A Griffiths, Nicola Hamilton, Paul Kelly, Mark O'Connor, Kerry Shea, Ian D Waddell, Donald J Ogilvie
After a DNA damage signal multiple polymers of ADP ribose attached to poly(ADP) ribose (PAR) polymerases (PARPs) are broken down by the enzyme poly(ADP) ribose glycohydrolase (PARG). Inhibition of PARG leads to a failure of DNA repair and small molecule inhibition of PARG has been a goal for many years. To determine whether biochemical inhibitors of PARG are active in cells we have designed an immunofluorescence assay to detect nuclear PAR after DNA damage. This 384-well assay is suitable for medium throughput high-content screening and can detect cell-permeable inhibitors of PARG from nM to µM potency...
2016: F1000Research
Elizaveta E Alemasova, Nina A Moor, Konstantin N Naumenko, Mikhail M Kutuzov, Maria V Sukhanova, Pavel E Pestryakov, Olga I Lavrik
Base excision repair (BER) is a flagship DNA repair system responsible for maintaining genome integrity. Apart from basal enzymes, this system involves several accessory factors essential for coordination and regulation of DNA processing during substrate channeling. Y-box-binding protein 1 (YB-1), a multifunctional factor that can interact with DNA, RNA, poly(ADP-ribose) and plenty of proteins including DNA repair enzymes, is increasingly considered as a non-canonical protein of BER. Here we provide quantitative characterization of YB-1 physical interactions with key BER factors such as PARP1, PARP2, APE1, NEIL1 and pol β and comparison of the full-length YB-1 and its C-terminally truncated nuclear form in regard to their binding affinities for BER proteins...
August 18, 2016: Biochimica et Biophysica Acta
Aaron Long, Ji H Park, Nina Klimova, Carol Fowler, David J Loane, Tibor Kristian
Several enzymes in cellular bioenergetics metabolism require NAD(+) as an essential cofactor for their activity. NAD(+) depletion following ischemic insult can result in cell death and has been associated with over-activation of poly-ADP-ribose polymerase PARP1 as well as an increase in NAD(+) consuming enzyme CD38. CD38 is an NAD(+) glycohydrolase that plays an important role in inflammatory responses. To determine the contribution of CD38 activity to the mechanisms of post-ischemic brain damage we subjected CD38 knockout (CD38KO) mice and wild-type (WT) mice to transient forebrain ischemia...
August 12, 2016: Neurochemical Research
Ibtissam Talhaoui, Natalia A Lebedeva, Gabriella Zarkovic, Christine Saint-Pierre, Mikhail M Kutuzov, Maria V Sukhanova, Bakhyt T Matkarimov, Didier Gasparutto, Murat K Saparbaev, Olga I Lavrik, Alexander A Ishchenko
Poly(ADP-ribose) polymerases (PARPs/ARTDs) use nicotinamide adenine dinucleotide (NAD(+)) to catalyse the synthesis of a long branched poly(ADP-ribose) polymer (PAR) attached to the acceptor amino acid residues of nuclear proteins. PARPs act on single- and double-stranded DNA breaks by recruiting DNA repair factors. Here, in in vitro biochemical experiments, we found that the mammalian PARP1 and PARP2 proteins can directly ADP-ribosylate the termini of DNA oligonucleotides. PARP1 preferentially catalysed covalent attachment of ADP-ribose units to the ends of recessed DNA duplexes containing 3'-cordycepin, 5'- and 3'-phosphate and also to 5'-phosphate of a single-stranded oligonucleotide...
July 28, 2016: Nucleic Acids Research
Chun-Xue Zhou, Xing-Quan Zhu, Hany M Elsheikha, Shuai He, Qian Li, Dong-Hui Zhou, Xun Suo
UNLABELLED: Toxoplasma gondii is a medically and economically important protozoan parasite. However, the molecular mechanisms of its sporulation remain largely unknown. Here, we applied iTRAQ coupled with 2D LC-MS/MS proteomic analysis to investigate the proteomic expression profile of T. gondii oocysts during sporulation. Of the 2095 non-redundant proteins identified, 587 were identified as differentially expressed proteins (DEPs). Based on Gene Ontology enrichment and KEGG pathway analyses the majority of these DEPs were found related to the metabolism of amino acids, carbon and energy...
October 4, 2016: Journal of Proteomics
Luca Palazzo, Casey M Daniels, Joanne E Nettleship, Nahid Rahman, Robert Lyle McPherson, Shao-En Ong, Kazuki Kato, Osamu Nureki, Anthony K L Leung, Ivan Ahel
ADP-ribosylation is a conserved post-translational protein modification that plays a role in all major cellular processes, particularly DNA repair, transcription, translation, stress response and cell death. Hence, dysregulation of ADP-ribosylation is linked to the physiopathology of several human diseases including cancers, diabetes and neurodegenerative disorders. Protein ADP-ribosylation can be reversed by the macrodomain-containing proteins PARG, TARG1, MacroD1 and MacroD2, which hydrolyse the ester bond known to link proteins to ADP-ribose as well as consecutive ADP-ribose subunits; targeting this bond can thus result in the complete removal of the protein modification or the conversion of poly(ADP-ribose) to mono(ADP-ribose)...
September 2016: FEBS Journal
Yingbiao Ji, Alexei V Tulin
Poly(ADP-ribosyl)ation of heterogeneous nuclear ribonucleoproteins (hnRNPs) regulates the posttranscriptional fate of RNA during development. Drosophila hnRNP A1, Hrp38, is required for germ line stem cell maintenance and oocyte localization. The mRNA targets regulated by Hrp38 are mostly unknown. We identified 428 Hrp38-associated gene transcripts in the fly ovary, including mRNA of the translational repressor Nanos. We found that Hrp38 binds to the 3' untranslated region (UTR) of Nanos mRNA, which contains a translation control element...
October 1, 2016: Molecular and Cellular Biology
Aurélia Noll, Giuditta Illuzzi, Jean-Christophe Amé, Françoise Dantzer, Valérie Schreiber
BACKGROUND: Poly(ADP-ribose) polymerase (PARP) inhibitors have entered the clinics for their promising anticancer effect as adjuvant in chemo- and radiotherapy and as single agent on BRCA-mutated tumours. Poly(ADP-ribose) glycohydrolase (PARG) deficiency was also shown to potentiate the cytotoxicity of genotoxic agents and irradiation. The aim of this study is to investigate the effect of PARG deficiency on BRCA1- and/or PTEN-deficient tumour cells. METHODS: Since no PARG inhibitors are available for in vivo studies, PARG was depleted by siRNA in several cancer cell lines, proficient or deficient for BRCA1 and/or PTEN...
2016: Cancer Cell International
Sachiko Yamashita, Masakazu Tanaka, Teruaki Sato, Chieri Ida, Narumi Ohta, Takashi Hamada, Taichi Uetsuki, Yoshisuke Nishi, Joel Moss, Masanao Miwa
Poly (ADP-ribose) (PAR) is rapidly synthesized by PAR polymerases (PARPs) upon activation by DNA single- and double-strand breaks. In this study, we examined the quantitative amount of PAR in HeLa cells cultured within the physiological temperatures below 41 °C for verification of the effect of shifting-up or -down the temperature from 37.0 °C on the DNA breaks, whether the temperature-shift caused breaks that could be monitored by the level of PAR. While PAR level did not change significantly when HeLa cells were cultured at 33...
August 5, 2016: Biochemical and Biophysical Research Communications
Girish R Chopda, Viraj Parge, Ganesh A Thakur, S John Gatley, Alexandros Makriyannis, Carol A Paronis
Daily treatment with cannabinoids results in tolerance to many, but not all, of their behavioral and physiologic effects. The present studies investigated the effects of 7-day exposure to 10 mg/kg daily of Δ(9)-tetrahydrocannabinol (THC) on the diuretic and antinociceptive effects of THC and the synthetic cannabinoid AM4054. Comparison studies determined diuretic responses to the κ-opioid agonist U50,488 and furosemide. After determination of control dose-response functions, mice received 10 mg/kg daily of THC for 7 days, and dose-response functions were re-determined 24 hours, 7 days, or 14 days later...
August 2016: Journal of Pharmacology and Experimental Therapeutics
Yukihide Watanabe, Panagiotis Papoutsoglou, Varun Maturi, Yutaro Tsubakihara, Michael O Hottiger, Carl-Henrik Heldin, Aristidis Moustakas
We previously established a mechanism of negative regulation of transforming growth factor β signaling mediated by the nuclear ADP-ribosylating enzyme poly-(ADP-ribose) polymerase 1 (PARP1) and the deribosylating enzyme poly-(ADP-ribose) glycohydrolase (PARG), which dynamically regulate ADP-ribosylation of Smad3 and Smad4, two central signaling proteins of the pathway. Here we demonstrate that the bone morphogenetic protein (BMP) pathway can also be regulated by the opposing actions of PARP1 and PARG. PARG positively contributes to BMP signaling and forms physical complexes with Smad5 and Smad4...
June 10, 2016: Journal of Biological Chemistry
Masato Mashimo, Joel Moss
Poly-ADP-ribosylation has been proposed to be a reversible protein modification, participating in diverse cellular functions including DNA repair, chromatin remodeling, genetic stability, mitosis, and cell death. Poly-ADP-ribosylation is initiated by the transfer of the ADP-ribose moiety of NAD+ primarily to the carboxyl groups of glutamate and aspartate and amino group of lysine residues in target proteins, followed by elongation of poly(ADP-ribose) (PAR) chains via -O-glycosidic (C-1"-C-2') ribose-ribose bonds...
April 19, 2016: Current Protein & Peptide Science
Julia P Vainonen, Alexey Shapiguzov, Aleksia Vaattovaara, Jaakko Kangasjärvi
Poly(ADP-ribos)ylation, originally described as a mechanism of DNA break repair, is now considered as part of a complex regulatory system involved in dynamic reorganization of chromatin structure, transcriptional control of gene expression and regulation of metabolism. In plants poly(ADP-ribos)ylation has received surprisingly little attention. It has been implicated in abiotic and biotic stress responses, cell cycle control and development; however, the molecular mechanisms and proteins involved are largely unknown...
April 19, 2016: Current Protein & Peptide Science
Alexandra I J Stowell, Dominic I James, Ian D Waddell, Neil Bennett, Caroline Truman, Ian M Hardern, Donald J Ogilvie
Poly(ADP-ribose) (PAR) polymers are transient post-translational modifications, and their formation is catalyzed by poly(ADP-ribose) polymerase (PARP) enzymes. A number of PARP inhibitors are in advanced clinical development for BRCA-mutated breast cancer, and olaparib has recently been approved for BRCA-mutant ovarian cancer; however, there has already been evidence of developed resistance mechanisms. Poly(ADP-ribose) glycohydrolase (PARG) catalyzes the hydrolysis of the endo- and exo-glycosidic bonds within the PAR polymers...
June 15, 2016: Analytical Biochemistry
Hui Gao, Olga A Goriacheva, Nadezda V Tarakina, Gleb B Sukhorukov
Microcapsules that can be efficiently loaded with small molecules and effectively released at the target area through the degradation of the capsule shells hold great potential for treating diseases. Traditional biodegradable polyelectrolyte (PE) capsules can be degraded by cells and eliminated from the body but fail to encapsulate drugs with small molecular weight. Here, we report a poly-l-arginine hydrochloride (PARG)/dextran sulfate sodium salt (DEXS)/silica (SiO2) composite capsule that can be destructed in cells and of which the in situ formed inorganic SiO2 enables loading of small model molecules, Rhodamine B (Rh-B)...
April 20, 2016: ACS Applied Materials & Interfaces
Mariana Schlesinger, Salomé C Vilchez Larrea, Teemu Haikarainen, Mohit Narwal, Harikanth Venkannagari, Mirtha M Flawiá, Lari Lehtiö, Silvia H Fernández Villamil
BACKGROUND: Poly(ADP-ribose) (PAR) metabolism participates in several biological processes such as DNA damage signaling and repair, which is a thoroughly studied function. PAR is synthesized by Poly(ADP-ribose) polymerase (PARP) and hydrolyzed by Poly(ADP-ribose) glycohydrolase (PARG). In contrast to human and other higher eukaryotes, Trypanosoma brucei contains only one PARP and PARG. Up to date, the function of these enzymes has remained elusive in this parasite. The aim of this work is to unravel the role that PAR plays in genotoxic stress response...
2016: Parasites & Vectors
Xuan Li, Xiyi Li, Zhiliang Zhu, Peiwu Huang, Zhixiong Zhuang, Jianjun Liu, Wei Gao, Yinpin Liu, Haiyan Huang
Benzo(a)pyrene (BaP) is a ubiquitously distributed environmental pollutant and known carcinogen, which can induce malignant transformation in rodent and human cells. Poly(ADP-ribose) glycohydrolase (PARG), the primary enzyme that catalyzes the degradation of poly(ADP-ribose) (PAR), has been known to play an important role in regulating DNA damage repair and maintaining genomic stability. Although PARG has been shown to be a downstream effector of BaP, the role of PARG in BaP induced carcinogenesis remains unclear...
2016: PloS One
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