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Parp1 dna

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https://www.readbyqxmd.com/read/28718810/dna2-an-important-player-in-dna-damage-response-or-just-another-dna-maintenance-protein
#1
REVIEW
Elzbieta Pawłowska, Joanna Szczepanska, Janusz Blasiak
The human DNA2 (DNA replication helicase/nuclease 2) protein is expressed in both the nucleus and mitochondria, where it displays ATPase-dependent nuclease and helicase activities. DNA2 plays an important role in the removing of long flaps in DNA replication and long-patch base excision repair (LP-BER), interacting with the replication protein A (RPA) and the flap endonuclease 1 (FEN1). DNA2 can promote the restart of arrested replication fork along with Werner syndrome ATP-dependent helicase (WRN) and Bloom syndrome protein (BLM)...
July 18, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28714034/inhibition-of-nampt-decreases-cell-growth-and-enhances-susceptibility-to-oxidative-stress
#2
Renhua Xu, Zhenwei Yuan, Lijuan Yang, Lele Li, Dan Li, Changjun Lv
Nicotinamide adenine dinucleotide (NAD) is an essential molecule for living organisms and plays a vital role in aging and age-associated diseases. In eukaryotic cells, cellular NAD is mainly generated by the scavenge pathway in which nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the formation of nicotinamide mononucleotide. Inhibition of NAMPT is a therapeutic strategy for cancer treatment. To explore the effects of NAMPT inhibition on cellular processes, cells were treated with 10 nM FK866, an NAMPT inhibitor, resulting in a decrease in the cellular NAD level, a lower growth rate, and enhanced susceptivity to oxidative stress as compared to the untreated cells...
July 6, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28710029/decreased-expression-level-of-ber-genes-in-alzheimer-s-disease-patients-is-not-derivative-of-their-dna-methylation-status
#3
Agnieszka Sliwinska, Przemysław Sitarek, Monika Toma, Piotr Czarny, Ewelina Synowiec, Renata Krupa, Paulina Wigner, Katarzyna Bialek, Dominik Kwiatkowski, Anna Korycinska, Ireneusz Majsterek, Janusz Szemraj, Piotr Galecki, Tomasz Sliwinski
BACKGROUND: Neurodegeneration in Alzheimer's disease can be caused by accumulation of oxidative DNA damage resulting from altered expression of genes involved in the base excision repair system (BER). Promoter methylation can affect the profile of BER genes expression. Decreased expression of BER genes was observed in the brains of AD patients. AIM OF THE STUDY: The aim of our study was to compare the expression and methylation profiles of six genes coding for proteins involved in BER, namely: hOGG1, APE1, MUTYH, NEIL1, PARP1 and XRCC1, in the peripheral blood cells of AD patients and healthy volunteers...
July 11, 2017: Progress in Neuro-psychopharmacology & Biological Psychiatry
https://www.readbyqxmd.com/read/28698968/inhibition-of-poly-adp-ribose-polymerase-1-enhances-gene-expression-of-selected-sirtuins-and-app-cleaving-enzymes-in-amyloid-beta-cytotoxicity
#4
Przemysław L Wencel, Walter J Lukiw, Joanna B Strosznajder, Robert Piotr Strosznajder
Poly(ADP-ribose) polymerases (PARPs) and sirtuins (SIRTs) are involved in the regulation of cell metabolism, transcription, and DNA repair. Alterations of these enzymes may play a crucial role in Alzheimer's disease (AD). Our previous results indicated that amyloid beta (Aβ) peptides and inflammation led to activation of PARP1 and cell death. This study focused on a role of PARP1 in the regulation of gene expression for SIRTs and beta-amyloid precursor protein (βAPP) cleaving enzymes under Aβ42 oligomers (AβO) toxicity in pheochromocytoma cells (PC12) in culture...
July 12, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28695510/poly-adp-ribose-dependent-chromatin-remodeling-in-dna-repair
#5
Théo Lebeaupin, Rebecca Smith, Sébastien Huet, Gyula Timinszky
The tightly packed and dynamic structure of chromatin can undergo major reorganization in response to endogenous or exogenous stimuli, such as the regulation of transcription or the cell cycle, or following DNA damage. A fast and local chromatin decondensation is observed upon DNA damage induced by laser micro-irradiation. This decondensation is under the control of poly(ADP-ribosyl)ation (PARylation) by PARP1, one of the first proteins recruited at the DNA damage sites. This chapter provides a step-by-step guide to perform and analyze chromatin decondensation upon DNA damage induction...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28692916/discovery-mechanism-and-metabolism-studies-of-2-3-difluorophenyl-linker-containing-parp1-inhibitors-with-enhanced-in%C3%A2-vivo-efficacy-for-cancer-therapy
#6
Wenhua Chen, Ne Guo, Minghui Qi, Haiying Dai, Minghuang Hong, Longfei Guan, Xiajuan Huan, Shanshan Song, Jinxue He, Yingqing Wang, Yong Xi, Xinying Yang, Yanyan Shen, Yi Su, Yiming Sun, Yinglei Gao, Yi Chen, Jian Ding, Yun Tang, Guobin Ren, Zehong Miao, Jian Li
Poly (ADP-ribose) polymerase 1 (PARP1) is overexpressed in a variety of cancers, especially breast and ovarian cancers, and tumor cell lines deficient in breast cancer gene 1/2 (BRCA1/2) are highly sensitive to PARP1 inhibition. In this study, with the help of molecular docking, we identified a novel series of 2,3-difluorophenyl-linker analogues (15-54) derived from olaparib (1) as PARP1 inhibitors. Lead optimization led to the identification of 47, which showed high selectivity and high potency against PARP1 enzyme (IC50 = 1...
June 27, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28687616/post-transcriptional-regulation-of-parg-mrna-by-hur-facilitates-dna-repair-and-resistance-to-parp-inhibitors
#7
Saswati N Chand, Mahsa Zarei, Matthew J Schiewer, Akshay R Kamath, Carmella Romeo, Shruti Lal, Joseph A Cozzitorto, Avinoam Nevler, Laura Scolaro, Eric Londin, Wei Jiang, Nicole Meisner-Kober, Michael J Pishvaian, Karen E Knudsen, Charles J Yeo, John M Pascal, Jordan M Winter, Jonathan R Brody
The majority of pancreatic ductal adenocarcinomas (PDA) rely on the mRNA stability factor HuR (ELAV-L1) to drive cancer growth and progression. Here we show that CRISPR-Cas9-mediated silencing of the HuR locus increases the relative sensitivity of PDA cells to PARP inhibitors (PARPi). PDA cells treated with PARPi stimulated translocation of HuR from the nucleus to the cytoplasm, specifically promoting stabilization of a new target, polyADP-ribose glycohydrolase (PARG) mRNA, by binding a unique sequence embedded in its 3' untranslated region (UTR)...
July 7, 2017: Cancer Research
https://www.readbyqxmd.com/read/28676700/the-multifaceted-roles-of-parp1-in-dna-repair-and-chromatin-remodelling
#8
REVIEW
Arnab Ray Chaudhuri, André Nussenzweig
Cells are exposed to various endogenous and exogenous insults that induce DNA damage, which, if unrepaired, impairs genome integrity and leads to the development of various diseases, including cancer. Recent evidence has implicated poly(ADP-ribose) polymerase 1 (PARP1) in various DNA repair pathways and in the maintenance of genomic stability. The inhibition of PARP1 is therefore being exploited clinically for the treatment of various cancers, which include DNA repair-deficient ovarian, breast and prostate cancers...
July 5, 2017: Nature Reviews. Molecular Cell Biology
https://www.readbyqxmd.com/read/28660007/micrornas-modulate-oxidative-stress-in-hypertension-through-parp-1-regulation
#9
Douglas F Dluzen, Yoonseo Kim, Paul Bastian, Yongqing Zhang, Elin Lehrmann, Kevin G Becker, Nicole Noren Hooten, Michele K Evans
Oxidative stress is thought to contribute to aging and age-related diseases, such as cardiovascular and neurodegenerative diseases, and is a risk factor for systemic arterial hypertension. Previously, we reported differential mRNA and microRNA (miRNA) expression between African American (AA) and white women with hypertension. Here, we found that the poly-(ADP-ribose) polymerase 1 (PARP-1), a DNA damage sensor protein involved in DNA repair and other cellular processes, is upregulated in AA women with hypertension...
2017: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/28655785/a-small-molecule-inhibitor-of-wee1-azd1775-synergizes-with-olaparib-by-impairing-homologous-recombination-and-enhancing-dna-damage-and-apoptosis-in-acute-leukemia
#10
Tamara B Garcia, Jonathan C Snedeker, Dmitry Baturin, Lori Gardner, Susan P Fosmire, Chengjing Zhou, Craig T Jordan, Sujatha Venkataraman, Rajeev Vibhakar, Christopher C Porter
Although some patients with acute leukemia have good prognoses, the prognosis of adult and pediatric patients who relapse or cannot tolerate standard chemotherapy is poor. Inhibition of WEE1 with AZD1775 has been shown to sensitize cancer cells to genotoxic chemotherapies including cytarabine in AML and T-ALL. Inhibition of WEE1 impairs homologous recombination by indirectly inhibiting BRCA2. Thus, we sought to determine if AZD1775 could sensitize cells to the PARP1/2 inhibitor olaparib. We found that combined treatment with AZD1775 and olaparib was synergistic in AML and ALL cells, and this combination impaired proliferative capacity upon drug withdrawal...
June 27, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28650317/serine-adp-ribosylation-reversal-by-the-hydrolase-arh3
#11
Ivan Ahel, Pietro Fontana, Juan José Bonfiglio, Luca Palazzo, Edward Bartlett, Ivan Matic
ADP-ribosylation (ADPr) is a posttranslational modification (PTM) of proteins that controls many cellular processes, including DNA repair, transcription, chromatin regulation and mitosis. A number of proteins catalyse the transfer and hydrolysis of ADPr, and also specify how and when the modification is conjugated to the targets. We recently discovered a new form of ADPr that is attached to serine residues in target proteins (Ser-ADPr) and showed that this PTM is specifically made by PARP1/HPF1 and PARP2/HPF1 complexes...
June 26, 2017: ELife
https://www.readbyqxmd.com/read/28634224/igh-myc-translocation-associates-with-brca2-deficiency-and-synthetic-lethality-to-parp1-inhibitors
#12
Silvia Maifrede, Kayla Martin, Paulina Podszywalow-Bartnicka, Katherine Sullivan, Samantha K Langer, Reza Nejadi, Yashodhara Dasgupta, Michael Hulse, Daniel Gritsyuk, Margaret Nieborowska-Skorska, Lena N Lupey-Green, Huaqing Zhao, Katarzyna Piwocka, Mariusz A Wasik, Italo Tempera, Tomasz Skorski
Burkitt lymphoma/leukemia (BL) cells carry t(8;14)(q24;q32) chromosomal translocation encoding IGH/MYC, which results in the constitutive expression of the MYC oncogene. Here, it is demonstrated that untreated and cytarabine (AraC)-treated IGH/MYC-positive BL cells accumulate a high number of potentially lethal DNA double-strand breaks (DSBs) and display low levels of the BRCA2 tumor suppressor protein, which is a key element of homologous recombination (HR)-mediated DSB repair. BRCA2 deficiency in IGH/MYC-positive cells was associated with diminished HR activity and hypersensitivity to poly (ADP-ribose) polymerase-1 (PARP1) inhibitors (olaparib, talazoparib) used alone or in combination with cytarabine in vitro...
June 20, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28624622/preclinical-anti-cancer-activity-and-multiple-mechanisms-of-action-of-a-cationic-silver-complex-bearing-n-heterocyclic-carbene-ligands
#13
Simon J Allison, Maria Sadiq, Efstathia Baronou, Patricia A Cooper, Chris Dunnill, Nikolaos T Georgopoulos, Ayşe Latif, Samantha Shepherd, Steve D Shnyder, Ian J Stratford, Richard T Wheelhouse, Charlotte E Willans, Roger M Phillips
Organometallic complexes offer the prospect of targeting multiple pathways that are important in cancer biology. Here, the preclinical activity and mechanism(s) of action of a silver-bis(N-heterocyclic carbine) complex (Ag8) were evaluated. Ag8 induced DNA damage via several mechanisms including topoisomerase I/II and thioredoxin reductase inhibition and induction of reactive oxygen species. DNA damage induction was consistent with cytotoxicity observed against proliferating cells and Ag8 induced cell death by apoptosis...
June 15, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28601509/olaparib-hydroxamic-acid-derivatives-as-dual-parp-and-hdac-inhibitors-for-cancer-therapy
#14
Zigao Yuan, Shaopeng Chen, Qinsheng Sun, Ning Wang, Dan Li, Shuangshuang Miao, Chunmei Gao, Yuzong Chen, Chunyan Tan, Yuyang Jiang
Olaparib was the first PARP inhibitor approved by the FDA for patients with BRCA-mutated ovarian cancer. Recent studies have demonstrated enhanced anticancer effects of combination therapy consisting of olaparib and HDAC inhibitors. Herein, based on rational drug design strategy, hydroxamic acid derivatives of olaparib were constructed as dual PARP and HDAC inhibitors. These hybrid compounds showed potent inhibitory activities against PARP1/2 and HDAC1/6 with IC50 values in the nanomolar range. Furthermore, compound P1 exhibited broad-spectrum antiproliferative activities in selected human cancer cell lines...
May 31, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28601074/role-of-glyceraldehyde-3-phosphate-dehydrogenase-gapdh-in-dna-repair
#15
REVIEW
A A Kosova, S N Khodyreva, O I Lavrik
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is widely known as a glycolytic enzyme. Nevertheless, various functions of GAPDH have been found that are unrelated to glycolysis. Some of these functions presume interaction of GAPDH with DNA, but the mechanism of its translocation to the nucleus is not fully understood. When in the nucleus, GAPDH participates in the initiation of apoptosis and transcription of genes involved in antiapoptotic pathways and cell proliferation and plays a role in the regulation of telomere length...
June 2017: Biochemistry. Biokhimii︠a︡
https://www.readbyqxmd.com/read/28599788/nr1d1-enhances-oxidative-dna-damage-by-inhibiting-parp1-activity
#16
Na-Lee Ka, Tae-Young Na, Mi-Ock Lee
Cancer cells exhibit an elevated intracellular level of reactive oxygen species (ROS) because of their accelerated metabolism, mitochondrial dysfunction, and antioxidant deficit. The oxidative stress in cancer cells may provide clinical benefits, which can be associated with a better response to anticancer therapies. Therefore, identifying the regulatory pathway of oxidative stress in cancer cells is important in the development of therapeutic targets that enhance sensitivity to ROS-generating anticancer therapies...
June 6, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28598207/the-relationship-between-single-nucleotide-polymorphisms-the-expression-of-dna-damage-response-genes-and-hepatocellular-carcinoma-in-a-polish-population
#17
Renata Krupa, Piotr Czarny, Paulina Wigner, Joanna Wozny, Maciej Jablkowski, Radzislaw Kordek, Janusz Szemraj, Tomasz Sliwinski
The molecular mechanism of hepatocellular carcinoma (HCC) is related to DNA damage caused by oxidative stress products induced by hepatitis B virus (HBV) or C (HCV) infection and exposure to environmental pollutants. Single-nucleotide polymorphisms (SNPs) of DNA damage response (DDR) genes may influence individual susceptibility to environmental risk factors and affect DNA repair efficacy, which, in turn, can influence the risk of HCC. The study evaluates a panel of 15 SNPs in 11 DDR genes (XRCC1, XRCC3, XPD, MUTYH, LIG1, LIG3, hOGG1, PARP1, NFIL1, FEN1, and APEX1) in 65 HCC patients, 50 HBV- and 50 HCV-infected non-cancerous patients, and 50 healthy controls...
June 9, 2017: DNA and Cell Biology
https://www.readbyqxmd.com/read/28587301/bridging-plant-and-human-radiation-response-and-dna-repair-through-an-in-silico-approach
#18
Zacharenia Nikitaki, Athanasia Pavlopoulou, Marcela Holá, Mattia Donà, Ioannis Michalopoulos, Alma Balestrazzi, Karel J Angelis, Alexandros G Georgakilas
The mechanisms of response to radiation exposure are conserved in plants and animals. The DNA damage response (DDR) pathways are the predominant molecular pathways activated upon exposure to radiation, both in plants and animals. The conserved features of DDR in plants and animals might facilitate interdisciplinary studies that cross traditional boundaries between animal and plant biology in order to expand the collection of biomarkers currently used for radiation exposure monitoring (REM) in environmental and biomedical settings...
June 6, 2017: Cancers
https://www.readbyqxmd.com/read/28582660/the-phytochemical-3-3-diindolylmethane-decreases-expression-of-ar-controlled-dna-damage-repair-genes-through-repressive-chromatin-modifications-and-is-associated-with-dna-damage-in-prostate-cancer-cells
#19
Zoraya Palomera-Sanchez, Gregory W Watson, Carmen P Wong, Laura M Beaver, David E Williams, Roderick H Dashwood, Emily Ho
Androgen receptor (AR) is a transcription factor involved in normal prostate physiology and prostate cancer (PCa) development. 3,3'-Diindolylmethane (DIM) is a promising phytochemical agent against PCa that affects AR activity and epigenetic regulators in PCa cells. However, whether DIM suppresses PCa via epigenetic regulation of AR target genes is unknown. We assessed epigenetic regulation of AR target genes in LNCaP PCa cells and showed that DIM treatment led to epigenetic suppression of AR target genes involved in DNA repair (PARP1, MRE11, DNA-PK)...
May 25, 2017: Journal of Nutritional Biochemistry
https://www.readbyqxmd.com/read/28566428/rational-combination-therapy-with-parp-and-mek-inhibitors-capitalizes-on-therapeutic-liabilities-in-ras-mutant-cancers
#20
Chaoyang Sun, Yong Fang, Jun Yin, Jian Chen, Zhenlin Ju, Dong Zhang, Xiaohua Chen, Christopher P Vellano, Kang Jin Jeong, Patrick Kwok-Shing Ng, Agda Karina B Eterovic, Neil H Bhola, Yiling Lu, Shannon N Westin, Jennifer R Grandis, Shiaw-Yih Lin, Kenneth L Scott, Guang Peng, Joan Brugge, Gordon B Mills
Mutant RAS has remained recalcitrant to targeted therapy efforts. We demonstrate that combined treatment with poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors and mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitors evokes unanticipated, synergistic cytotoxic effects in vitro and in vivo in multiple RAS mutant tumor models across tumor lineages where RAS mutations are prevalent. The effects of PARP and MEK inhibitor combinations are independent of BRCA1/2 and p53 mutation status, suggesting that the synergistic activity is likely to be generalizable...
May 31, 2017: Science Translational Medicine
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