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Parp1 dna

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https://www.readbyqxmd.com/read/27923837/the-nci-60-methylome-and-its-integration-into-cellminer
#1
William C Reinhold, Sudhir Varma, Margot Sunshine, Vinodh Rajapakse, Augustin Luna, Kurt W Kohn, Holly Stevenson, Yonghong Wang, Holger Heyn, Vanesa Nogales, Sebastian Moran, David J Goldstein, James H Doroshow, Paul S Meltzer, Manel Esteller, Yves Pommier
A unique resource for systems pharmacology and genomic studies is the NCI-60 cancer cell line panel, which provides data for the largest publicly available library of compounds with cytotoxic activity (~21,000 compounds), including 108 FDA-approved and 70 clinical trial drugs as well as genomic data, including whole-exome sequencing, gene and microRNA transcripts, DNA copy number, and protein levels. Here we provide the first readily usable genome-wide DNA methylation database for the NCI-60, including 485,577 probes from the Infinium HumanMethylation450k BeadChip array, which yielded DNA methylation signatures for 17,559 genes integrated into our open access CellMiner version 2...
December 6, 2016: Cancer Research
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
#2
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
#3
REVIEW
Fabio Ciccarone, Michele Zampieri, Paola Caiafa
Epigenetic events include reversible modifications of DNA and histone tails driving higher-order 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/27902462/the-synthetic-lethal-killing-of-rad54b-deficient-colorectal-cancer-cells-by-parp1-inhibition-is-enhanced-with-sod1-inhibition
#4
Erin N McAndrew, Chloe C Lepage, Kirk J McManus
Colorectal cancer (CRC) is a leading cause of cancer-related death throughout the world. Despite improved screening efforts, most CRCs are diagnosed at late stages when surgery alone is not curative. Moreover, the low 5-year survival rate (~8-13%) for those living with stage IV CRC highlights the need for better treatment options. Many current chemotherapeutic approaches are non-specific and associated with side effects due to their tendency to target both normal and cancer cells. To address this issue, synthetic lethal (SL) approaches are now being explored in cancer and are defined as the lethal combination of two independently viable mutations/deletions...
November 26, 2016: Oncotarget
https://www.readbyqxmd.com/read/27890643/coordination-of-dna-single-strand-break-repair
#5
Rachel Abbotts, David M Wilson
The genetic material of all organisms is susceptible to modification. In some instances, these changes are programmed, such as the formation of DNA double strand breaks during meiotic recombination to generate gamete variety or class switch recombination to create antibody diversity. However, in most cases, genomic damage is potentially harmful to the health of the organism, contributing to disease and aging by promoting deleterious cellular outcomes. A proportion of DNA modifications are caused by exogenous agents, both physical (namely ultraviolet sunlight and ionizing radiation) and chemical (such as benzopyrene, alkylating agents, platinum compounds and psoralens), which can produce numerous forms of DNA damage, including a range of "simple" and helix-distorting base lesions, abasic sites, crosslinks and various types of phosphodiester strand breaks...
November 24, 2016: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/27866211/single-nucleotide-polymorphisms-of-genes-involved-in-repair-of-oxidative-dna-damage-and-the-risk-of-recurrent-depressive-disorder
#6
Piotr Czarny, Dominik Kwiatkowski, Monika Toma, Piotr Gałecki, Agata Orzechowska, Kinga Bobińska, Anna Bielecka-Kowalska, Janusz Szemraj, Michael Berk, George Anderson, Tomasz Śliwiński
BACKGROUND Depressive disorder, including recurrent type (rDD), is accompanied by increased oxidative stress and activation of inflammatory pathways, which may induce DNA damage. This thesis is supported by the presence of increased levels of DNA damage in depressed patients. Such DNA damage is repaired by the base excision repair (BER) pathway. BER efficiency may be influenced by polymorphisms in BER-related genes. Therefore, we genotyped nine single-nucleotide polymorphisms (SNPs) in six genes encoding BER proteins...
November 20, 2016: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
https://www.readbyqxmd.com/read/27866150/crispr-cas9-induced-double-strand-break-repair-in-arabidopsis-non-homologous-end-joining-mutants
#7
Hexi Shen, Gary D Strunks, Bart J P M Klemann, Paul J J Hooykaas, Sylvia de Pater
Double-strand breaks (DSBs) are one of the most harmful DNA lesions. Cells utilize two main pathways for DSB repair: homologous recombination (HR) and non-homologous end-joining (NHEJ). NHEJ can be subdivided into the KU-dependent classical NHEJ (c-NHEJ) and the more error-prone KU-independent backup-NHEJ (b-NHEJ) pathways, involving the poly (ADP-ribose) polymerases (PARPs). However, in absence of these factors, cells still seem able to adequately maintain genome integrity, suggesting the presence of other b-NHEJ repair factors or pathways independent from KU and PARPs...
November 18, 2016: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/27863399/different-non-synonymous-polymorphisms-modulate-the-interaction-of-the-wrn-protein-to-its-protein-partners-and-its-enzymatic-activities
#8
Jean-Philippe Gagné, Sophie Lachapelle, Chantal Garand, Serges P Tsofack, Yan Coulombe, Marie-Christine Caron, Guy G Poirier, Jean-Yves Masson, Michel Lebel
Werner syndrome (WS) is characterized by the premature onset of several age-associated pathologies including cancer. The protein defective in WS patients (WRN) is a helicase/exonuclease involved in DNA replication and repair. Here, we present the results of a large-scale proteome analysis that has been undertaken to determine protein partners of different polymorphic WRN proteins found with relatively high prevalence in the human population. We expressed different fluorescently tagged-WRN (eYFP-WRN) variants in human 293 embryonic kidney cells (HEK293) and used a combination of affinity-purification and mass spectrometry to identify different compositions of WRN-associated protein complexes...
November 14, 2016: Oncotarget
https://www.readbyqxmd.com/read/27857998/a-parp1-erk2-synergism-is-required-for-stimulation-induced-expression-of-immediate-early-genes
#9
M Cohen-Armon
A PARP1-Erk2 synergism was required to generate synaptic long-term potentiation in the CA3-CA1 hippocampal connections. This molecular mechanism was associated with the recently identified pivotal role of polyADP-ribosylation in learning. High frequency electrical stimulation of cortical and hippocampal neurons induced binding of phosphorylated Erk2 (transported into the nucleus) to the nuclear protein PARP1. PARP1-Erk2 binding induced PARP1 activation and polyADP-ribosylation of its prominent substrate, linker histone H1...
2016: Gene & Translational Bioinformatics
https://www.readbyqxmd.com/read/27847302/poly-adp-ribose-polymerase-parp-inhibition-and-anticancer-activity-of-simmiparib-a-new-inhibitor-undergoing-clinical-trials
#10
Bo Yuan, Na Ye, Shan-Shan Song, Yu-Ting Wang, Zilan Song, Hua-Dong Chen, Chuan-Huizi Chen, Xia-Juan Huan, Ying-Qing Wang, Yi Su, Yan-Yan Shen, Yi-Ming Sun, Xin-Ying Yang, Yi Chen, Shi-Yan Guo, Yong Gan, Zhi-Wei Gao, Xiao-Yan Chen, Jian Ding, Jin-Xue He, Ao Zhang, Ze-Hong Miao
Poly(ADP-ribose)polymerase (PARP)1/2 inhibitors have been proved to be clinically effective anticancer drugs. Here we report a new PARP1/2 inhibitor, simmiparib, displaying apparently improved preclinical anticancer activities relative to the first approved inhibitor olaparib. Simmiparib inhibited PARP1/2 approximately 2-fold more potently than olaparib, with more than 90-fold selectivity over the other tested PARP family members. Simmiparib and olaparib caused similar cellular PARP1-DNA trapping. Simmiparib selectively induced the accumulation of DNA double-strand breaks, G2/M arrest and apoptosis in homologous recombination repair (HR)-deficient cells...
November 12, 2016: Cancer Letters
https://www.readbyqxmd.com/read/27808039/neurodegeneration-in-accelerated-aging
#11
Moren Scheibye-Knudsen
The growing proportion of elderly people represents an increasing economic burden, not least because of age-associated diseases that pose a significant cost to the health service. Finding possible interventions to age-associated disorders therefore have wide ranging implications. A number of genetically defined accelerated aging diseases have been characterized that can aid in our understanding of aging. Interestingly, all these diseases are associated with defects in the maintenance of our genome. A subset of these disorders, Cockayne syndrome, Xeroderma pigmentosum group A and ataxia-telangiectasia, show neurological involvement reminiscent of what is seen in primary human mitochondrial diseases...
November 2016: Danish Medical Journal
https://www.readbyqxmd.com/read/27806302/telomere-internal-double-strand-breaks-are-repaired-by-homologous-recombination-and-parp1-lig3-dependent-end-joining
#12
Ylli Doksani, Titia de Lange
Shelterin protects chromosome ends from the DNA damage response. Although the mechanism of telomere protection has been studied extensively, the fate of double-strand breaks (DSBs) inside telomeres is not known. Here, we report that telomere-internal FokI-induced DSBs activate ATM kinase-dependent signaling in S-phase but are well tolerated and repaired efficiently. Homologous recombination contributes to repair, leading to increased telomere length heterogeneity typical of the alternative lengthening of telomeres (ALT) pathway...
November 1, 2016: Cell Reports
https://www.readbyqxmd.com/read/27791127/cockayne-syndrome-group-a-and-b-proteins-converge-on-transcription-linked-resolution-of-non-b-dna
#13
Morten Scheibye-Knudsen, Anne Tseng, Martin Borch Jensen, Karsten Scheibye-Alsing, Evandro Fei Fang, Teruaki Iyama, Sanjay Kumar Bharti, Krisztina Marosi, Lynn Froetscher, Henok Kassahun, David Mark Eckley, Robert W Maul, Paul Bastian, Supriyo De, Soumita Ghosh, Hilde Nilsen, Ilya G Goldberg, Mark P Mattson, David M Wilson, Robert M Brosh, Myriam Gorospe, Vilhelm A Bohr
Cockayne syndrome is a neurodegenerative accelerated aging disorder caused by mutations in the CSA or CSB genes. Although the pathogenesis of Cockayne syndrome has remained elusive, recent work implicates mitochondrial dysfunction in the disease progression. Here, we present evidence that loss of CSA or CSB in a neuroblastoma cell line converges on mitochondrial dysfunction caused by defects in ribosomal DNA transcription and activation of the DNA damage sensor poly-ADP ribose polymerase 1 (PARP1). Indeed, inhibition of ribosomal DNA transcription leads to mitochondrial dysfunction in a number of cell lines...
November 1, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27787517/parp1-regulates-the-protein-stability-and-proapoptotic-function-of-hipk2
#14
Jong-Ryoul Choi, Ki Soon Shin, Cheol Yong Choi, Shin Jung Kang
Homeodomain-interacting protein kinase 2 (HIPK2) is a nuclear serine/threonine kinase that functions in DNA damage response and development. In the present study, we propose that the protein stability and proapoptotic function of HIPK2 are regulated by poly(ADP-ribose) polymerase 1 (PARP1). We present evidence indicating that PARP1 promotes the proteasomal degradation of HIPK2. The tryptophan-glycine-arginine (WGR) domain of PARP1 was necessary and sufficient for the promotion of HIPK2 degradation independently of the PARP1 enzymatic activity...
October 27, 2016: Cell Death & Disease
https://www.readbyqxmd.com/read/27756336/identification-of-brca1-like-triple-negative-breast-cancers-by-quantitative-multiplex-ligation-dependent-probe-amplification-mlpa-analysis-of-brca1-associated-chromosomal-regions-a-validation-study
#15
Eva Gross, Harm van Tinteren, Zhou Li, Sandra Raab, Christina Meul, Stefanie Avril, Nadja Laddach, Michaela Aubele, Corinna Propping, Apostolos Gkazepis, Manfred Schmitt, Alfons Meindl, Petra M Nederlof, Marion Kiechle, Esther H Lips
BACKGROUND: Triple-negative breast cancer (TNBC) with a BRCA1-like molecular signature has been demonstrated to remarkably respond to platinum-based chemotherapy and might be suited for a future treatment with poly(ADP-ribose)polymerase (PARP) inhibitors. In order to rapidly assess this signature we have previously developed a multiplex-ligation-dependent probe amplification (MLPA)-based assay. Here we present an independent validation of this assay to confirm its important clinical impact...
October 19, 2016: BMC Cancer
https://www.readbyqxmd.com/read/27748893/crosstalk-between-autophagy-and-intracellular-radiation-response-review
#16
Lelin Hu, Hao Wang, Li Huang, Yong Zhao, Junjie Wang
Autophagy induced by radiation is critical to cell fate decision. Evidence now sheds light on the importance of autophagy induced by cancer radiotherapy. Traditional view considers radiation can directly or indirectly damage DNA which can activate DNA damage the repair signaling pathway, a large number of proteins participating in DNA damage repair signaling pathway such as p53, ATM, PARP1, FOXO3a, mTOR and SIRT1 involved in autophagy regulation. However, emerging recent evidence suggests radiation can also cause injury to extranuclear targets such as plasma membrane, mitochondria and endoplasmic reticulum (ER) and induce accumulation of ceramide, ROS, and Ca2+ concentration which activate many signaling pathways to modulate autophagy...
October 5, 2016: International Journal of Oncology
https://www.readbyqxmd.com/read/27742776/germline-missense-pathogenic-variants-in-the-brca1-brct-domain-p-gly1706glu-and-p-ala1708glu-increase-cellular-sensitivity-to-parp-inhibitor-olaparib-by-a-dominant-negative-effect
#17
Tereza Vaclová, Nicholas T Woods, Diego Megías, Sergio Gomez-Lopez, Fernando Setién, José María García Bueno, José Antonio Macías, Alicia Barroso, Miguel Urioste, Manel Esteller, Alvaro N A Monteiro, Javier Benítez, Ana Osorio
BRCA1-deficient cells show defects in DNA repair and rely on other members of the DNA repair machinery, which makes them sensitive to PARP inhibitors (PARPi). Although carrying a germline pathogenic variant in BRCA1/2 is the best determinant of response to PARPi, a significant percentage of the patients do not show sensitivity and/or display increased toxicity to the agent. Considering previously suggested mutation-specific BRCA1 haploinsufficiency, we aimed to investigate whether there are any differences in cellular response to PARPi Olaparib depending on the BRCA1 mutation type...
October 13, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/27741411/nuclear-pten-interferes-with-binding-of-ku70-at-double-strand-breaks-through-post-translational-poly-adp-ribosyl-ation
#18
Jiawei Guan, Qian Zhao, Weifeng Mao
PTEN is a tumor suppressor gene characterized as a phosphatase that antagonizes the phosphatidylinositol 3-kinase signaling pathway in the cytoplasm. Nuclear PTEN plays roles in chromosomal stability, in which the double-strand breaks (DSB) repair mediated by homologous recombination (HR) and non-homologous end joining (NHEJ) is critical. Herein, the role of nuclear PTEN in DSB repair and the underlying molecular mechanism was investigated in this study. Using human breast cancer BT549 and MDA-MB-231 cell lines, we reveal a specific feature of PTEN that controls poly(ADP-ribosyl)ation of Ku70 and interferes with binding of Ku70 at DSB...
December 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27733626/the-poly-adp-ribose-dependent-chromatin-remodeler-alc1-induces-local-chromatin-relaxation-upon-dna-damage
#19
Hafida Sellou, Théo Lebeaupin, Catherine Chapuis, Rebecca Smith, Anna Hegele, Hari R Singh, Marek Kozlowski, Sebastian Bultmann, Andreas G Ladurner, Gyula Timinszky, Sébastien Huet
Chromatin relaxation is one of the earliest cellular responses to DNA damage. However, what determines these structural changes, including their ATP requirement, is not well understood. Using live-cell imaging and laser microirradiation to induce DNA lesions, we show that the local chromatin relaxation at DNA damage sites is regulated by PARP1 enzymatic activity. We also report that H1 is mobilized at DNA damage sites, but, since this mobilization is largely independent of poly(ADP-ribosyl)ation, it cannot solely explain the chromatin relaxation...
December 1, 2016: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/27728808/enhancing-the-cytotoxic-effects-of-parp-inhibitors-with-dna-demethylating-agents-a-potential-therapy-for-cancer
#20
Nidal E Muvarak, Khadiza Chowdhury, Limin Xia, Carine Robert, Eun Yong Choi, Yi Cai, Marina Bellani, Ying Zou, Zeba N Singh, Vu H Duong, Tyler Rutherford, Pratik Nagaria, Søren M Bentzen, Michael M Seidman, Maria R Baer, Rena G Lapidus, Stephen B Baylin, Feyruz V Rassool
Poly (ADP-ribose) polymerase inhibitors (PARPis) are clinically effective predominantly for BRCA-mutant tumors. We introduce a mechanism-based strategy to enhance PARPi efficacy based on DNA damage-related binding between DNA methyltransferases (DNMTs) and PARP1. In acute myeloid leukemia (AML) and breast cancer cells, DNMT inhibitors (DNMTis) alone covalently bind DNMTs into DNA and increase PARP1 tightly bound into chromatin. Low doses of DNMTis plus PARPis, versus each drug alone, increase PARPi efficacy, increasing amplitude and retention of PARP1 directly at laser-induced DNA damage sites...
October 10, 2016: Cancer Cell
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