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DNA damage response

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https://www.readbyqxmd.com/read/27922010/mek-inhibitors-block-growth-of-lung-tumours-with-mutations-in-ataxia-telangiectasia-mutated
#1
Michal Smida, Ferran Fece de la Cruz, Claudia Kerzendorfer, Iris Z Uras, Barbara Mair, Abdelghani Mazouzi, Tereza Suchankova, Tomasz Konopka, Amanda M Katz, Keren Paz, Katalin Nagy-Bojarszky, Markus K Muellner, Zsuzsanna Bago-Horvath, Eric B Haura, Joanna I Loizou, Sebastian M B Nijman
Lung cancer is the leading cause of cancer deaths, and effective treatments are urgently needed. Loss-of-function mutations in the DNA damage response kinase ATM are common in lung adenocarcinoma but directly targeting these with drugs remains challenging. Here we report that ATM loss-of-function is synthetic lethal with drugs inhibiting the central growth factor kinases MEK1/2, including the FDA-approved drug trametinib. Lung cancer cells resistant to MEK inhibition become highly sensitive upon loss of ATM both in vitro and in vivo...
December 6, 2016: Nature Communications
https://www.readbyqxmd.com/read/27919340/consequences-of-irradiation-on-adult-spermatogenesis-between-infertility-and-hereditary-risk
#2
Henri-Baptiste Marjault, Isabelle Allemand
DNA damage response in adult spermatogenic cells should limit the propagation of mutations to the offspring, without being detrimental to fertility. In differentiating spermatogenic cells, the genomic instability is limited in time, whereas in spermatogonial stem cells it can be maintained all along life. Spermatogonial stem cells are long-lived cells that support normal germ cell differentiation and must be preserved throughout life. However after irradiation spermatogenesis recovery can be impaired as a consequence of the radiation-induced decline in spermatogonial stem cell...
October 2016: Mutation Research
https://www.readbyqxmd.com/read/27917412/zbp1-dai-is-an-innate-sensor-of-influenza-virus-triggering-the-nlrp3-inflammasome-and-programmed-cell-death-pathways
#3
Teneema Kuriakose, Si Ming Man, R K Subbarao Malireddi, Rajendra Karki, Sannula Kesavardhana, David E Place, Geoffrey Neale, Peter Vogel, Thirumala-Devi Kanneganti
The interferon-inducible protein Z-DNA binding protein 1 (ZBP1, also known as DNA-dependent activator of IFN-regulatory factors (DAI) and DLM-1) was identified as a dsDNA sensor, which instigates innate immune responses. However, this classification has been disputed and whether ZBP1 functions as a pathogen sensor during an infection has remained unknown. Herein, we demonstrated ZBP1-mediated sensing of the influenza A virus (IAV) proteins NP and PB1, triggering cell death and inflammatory responses via the RIPK1-RIPK3-Caspase-8 axis...
August 5, 2016: Science Immunology
https://www.readbyqxmd.com/read/27917193/dna-damage-response-and-autophagy-a-meaningful-partnership
#4
REVIEW
Aristides G Eliopoulos, Sophia Havaki, Vassilis G Gorgoulis
Autophagy and the DNA damage response (DDR) are biological processes essential for cellular and organismal homeostasis. Herein, we summarize and discuss emerging evidence linking DDR to autophagy. We highlight published data suggesting that autophagy is activated by DNA damage and is required for several functional outcomes of DDR signaling, including repair of DNA lesions, senescence, cell death, and cytokine secretion. Uncovering the mechanisms by which autophagy and DDR are intertwined provides novel insight into the pathobiology of conditions associated with accumulation of DNA damage, including cancer and aging, and novel concepts for the development of improved therapeutic strategies against these pathologies...
2016: Frontiers in Genetics
https://www.readbyqxmd.com/read/27916662/acetylation-of-pcna-sliding-surface-by-eco1-promotes-genome-stability-through-homologous-recombination
#5
Pierre Billon, Jian Li, Jean-Philippe Lambert, Yizhang Chen, Véronique Tremblay, Joseph S Brunzelle, Anne-Claude Gingras, Alain Verreault, Tomohiko Sugiyama, Jean-Francois Couture, Jacques Côté
During DNA replication, proliferating cell nuclear antigen (PCNA) adopts a ring-shaped structure to promote processive DNA synthesis, acting as a sliding clamp for polymerases. Known posttranslational modifications function at the outer surface of the PCNA ring to favor DNA damage bypass. Here, we demonstrate that acetylation of lysine residues at the inner surface of PCNA is induced by DNA lesions. We show that cohesin acetyltransferase Eco1 targets lysine 20 at the sliding surface of the PCNA ring in vitro and in vivo in response to DNA damage...
November 16, 2016: Molecular Cell
https://www.readbyqxmd.com/read/27915381/regulation-of-non-homologous-end-joining-via-post-translational-modifications-of-components-of-the-ligation-step
#6
REVIEW
Kristína Durdíková, Miroslav Chovanec
DNA double-strand breaks are the most serious type of DNA damage and non-homologous end joining (NHEJ) is an important pathway for their repair. In Saccharomyces cerevisiae, three complexes mediate the canonical NHEJ pathway, Ku (Ku70/Ku80), MRX (Mre11/Rad50/Xrs2) and DNA ligase IV (Dnl4/Lif1). Mammalian NHEJ is more complex, primarily as a consequence of the fact that more factors are involved in the process, and also because higher chromatin organization and more complex regulatory networks exist in mammals...
December 3, 2016: Current Genetics
https://www.readbyqxmd.com/read/27915243/signaling-pathways-of-replication-stress-in-yeast
#7
Benjamin Pardo, Laure Crabbé, Philippe Pasero
Eukaryotic cells activate the S-phase checkpoint in response to a variety of events affecting the progression of replication forks, collectively referred to as replication stress. This signaling pathway is divided in two branches: the DNA damage checkpoint (DDC) and the DNA replication checkpoint (DRC). Both pathways are activated by the sensor kinase Mec1 and converge on the effector kinase Rad53. However, the DDC operates throughout the cell cycle and depends on the checkpoint mediator Rad9 to activate Rad53, whereas the DRC is specific to S phase and is mediated by Mrc1 and other fork components to signal replication impediments...
December 2, 2016: FEMS Yeast Research
https://www.readbyqxmd.com/read/27915231/predominant-role-of-dna-polymerase-eta-and-p53-dependent-translesion-synthesis-in-the-survival-of-ultraviolet-irradiated-human-cells
#8
Leticia K Lerner, Guilherme Francisco, Daniela T Soltys, Clarissa R R Rocha, Annabel Quinet, Alexandre T Vessoni, Ligia P Castro, Taynah I P David, Silvina O Bustos, Bryan E Strauss, Vanesa Gottifredi, Anne Stary, Alain Sarasin, Roger Chammas, Carlos F M Menck
Genome lesions trigger biological responses that help cells manage damaged DNA, improving cell survival. Pol eta is a translesion synthesis (TLS) polymerase that bypasses lesions that block replicative polymerases, avoiding continued stalling of replication forks, which could lead to cell death. p53 also plays an important role in preventing cell death after ultraviolet (UV) light exposure. Intriguingly, we show that p53 does so by favoring translesion DNA synthesis by pol eta. In fact, the p53-dependent induction of pol eta in normal and DNA repair-deficient XP-C human cells after UV exposure has a protective effect on cell survival after challenging UV exposures, which was absent in p53- and Pol H-silenced cells...
December 2, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27915178/anticancer-copper-pyridine-benzimidazole-complexes-ros-generation-biomolecule-interactions-and-cytotoxicity
#9
Kathleen E Prosser, Stephanie W Chang, Felix Saraci, Phuc H Le, Charles J Walsby
The Cu(II) complex CuCl2(pbzH), pbzH=2-(2-pyridyl)benzimidazole, and derivatives modified at the non-coordinated nitrogen of the benzimidazole fragment, have been studied as anticancer agents. These compounds show promising cytotoxicity against A549 adenocarcinomic alveolar basal epithelial cells with IC50 values in the range of 5-10μM. Importantly, this activity is higher than either CuCl2·2H2O or the individual ligands, demonstrating that ligand coordination to the Cu(II) centres of the complexes is required for full activity...
November 5, 2016: Journal of Inorganic Biochemistry
https://www.readbyqxmd.com/read/27914352/searching-for-novel-modes-of-toxic-actions-of-oil-spill-using-e-%C3%A2-coli-live-cell-array-reporter-system-a-hebei-spirit-oil-spill-study
#10
Dawoon Jung, Miao Guan, Sangwoo Lee, Cheolmin Kim, Hyesoo Shin, Seongjin Hong, Un Hyuk Yim, Won Joon Shim, John P Giesy, Jong Seong Khim, Xiaowei Zhang, Kyungho Choi
Oil is a complex mixture of numerous compounds. Therefore, oil spills near shore can cause various adverse effects on coastal ecosystems. However, most toxicological assessments conducted on oil spill sites have focused on limited modes of toxic actions. In the present study, we utilized the Escherichia coli (E. coli) live cell array system (LCA) to identify novel modes of toxicities of the oil spill-affected sediments. For this purpose, sediment samples were collected from an area heavily polluted by Hebei Spirit oil spill (HSOS) incident of 2007...
November 30, 2016: Chemosphere
https://www.readbyqxmd.com/read/27914347/differential-crosstalk-between-global-dna-methylation-and-metabolomics-associated-with-cell-type-specific-stress-response-by-pristine-and-functionalized-mwcnt
#11
Nivedita Chatterjee, Jisu Yang, Dahye Yoon, Suhkmann Kim, Sang-Woo Joo, Jinhee Choi
The present study endeavored to evaluate the comprehensive mechanisms of MWCNT-induced toxicity with particular emphasis on understanding cell specificity in relation to surface functionalization of MWCNT. Following treatment with differentially functionalized (hydroxylation/carboxylation) MWCNT on human bronchial epithelial (BEAS-2B) and human hepatoma (HepG2) cell lines, intracellular uptake, various toxicological end points, global metabolomics profiling and DNA methylation were evaluated. Herein, the comparative in vitro studies ascertained that surface functionalization diminished the toxic potentiality of MWCNT in respect of their pristine counterpart...
November 9, 2016: Biomaterials
https://www.readbyqxmd.com/read/27913897/rainbow-trout-oncorhynchus-mykiss-pro-oxidant-and-genotoxic-responses-following-acute-and-chronic-exposure-to-the-antibiotic-oxytetracycline
#12
Sara Rodrigues, Sara C Antunes, Alberto T Correia, Bruno Nunes
Oxytetracycline (OTC), an antibacterial agent, is extensively used in aquaculture practices all over the world, but also in human and veterinary medicines. Because of its intensive use, low rates of absorption by treated animals, inadequate disposal, and low efficiency of removal in wastewater treatment plants, the potential harmful effects on aquatic organisms are of great concern. This work aimed to assess the effects of this antibiotic in rainbow trout, following both acute and chronic exposures. Catalase (CAT), total glutathione peroxidase (GPx), glutathione reductase (GRed) activities and lipid peroxidation (TBARS levels) were quantified as oxidative stress biomarkers, in gills and liver...
December 2, 2016: Ecotoxicology
https://www.readbyqxmd.com/read/27913495/germ-line-mutations-associated-with-leukemias
#13
Christopher C Porter
Several genetic syndromes have long been associated with a predisposition to the development of leukemia, including bone marrow failure syndromes, Down syndrome, and Li Fraumeni syndrome. Recent work has better defined the leukemia risk and outcomes in these syndromes. Also, in the last several years, a number of other germ line mutations have been discovered to define new leukemia predisposition syndromes, including ANKRD26, GATA2, PAX5, ETV6, and DDX41 In addition, data suggest that a substantial proportion of patients with therapy related leukemias harbor germ line mutations in DNA damage response genes such as BRCA1/2 and TP53 Recognition of clinical associations, acquisition of a thorough family history, and high index-of-suspicion are critical in the diagnosis of these leukemia predisposition syndromes...
December 2, 2016: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/27913296/regulation-of-skeletal-muscle-insulin-stimulated-signaling-through-the-mek-redd1-mtor-axis
#14
Cory M Dungan, David L Williamson
Recent findings in adipocytes suggest that mitogen-activated protein kinase (MAPK)/extracellular-regulated signaling kinase (ERK) kinase 1/2 (MEK1/2) signaling regulates regulated in development and DNA damage 1 (REDD1) protein expression. Similarly, our previous work show that a lack of REDD1 protein expression, and associated hyperactive basal mechanistic target of rapamycin (mTOR) signaling, limits skeletal muscle's response to insulin. Therefore, we sought to determine: 1) if MEK1/2 inhibition is sufficient to reduce REDD1 protein expression and subsequently insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation via negative feedback of hyperactive mTOR in REDD1 wild-type (WT) mice and 2) if rapamycin-mediated mTOR inhibition is sufficient to improve IRS-1 tyrosine phosphorylation in REDD1 knockout (KO) mice...
November 29, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27911668/association-of-5-hydroxymethylation-and-5-methylation-of-dna-cytosine-with-tissue-specific-gene-expression
#15
V K Chaithanya Ponnaluri, Kenneth C Ehrlich, Guoqiang Zhang, Michelle Lacey, Douglas Johnston, Sriharsa Pradhan, Melanie Ehrlich
Differentially methylated or hydroxymethylated regions (DMRs) in mammalian DNA are often associated with tissue-specific gene expression but the functional relationships are still being unraveled. To elucidate these relationships, we studied 16 human genes containing myogenic DMRs by analyzing profiles of their epigenetics and transcription and quantitatively assaying 5-hydroxymethylcytosine (5 hmC) and 5-methylcytosine (5 mC) at specific sites in these genes in skeletal muscle (SkM), myoblasts, heart, brain, and diverse other samples...
December 2, 2016: Epigenetics: Official Journal of the DNA Methylation Society
https://www.readbyqxmd.com/read/27910856/acquired-resistance-of-pancreatic-cancer-cells-to-cisplatin-is-multifactorial-with-cell-context-dependent-involvement-of-resistance-genes
#16
R Mezencev, L V Matyunina, G T Wagner, J F McDonald
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal of malignancies, in large measure, due to the propensity of PDAC cells to acquire resistance to chemotherapeutic agents. A better understanding of the molecular basis of acquired resistance is a major focus of contemporary PDAC research. We report here the results of a study to independently develop cisplatin resistance in two distinct parental PDAC cell lines, AsPC1 and BxPC3, and to subsequently examine the molecular mechanisms associated with the acquired resistance...
December 2, 2016: Cancer Gene Therapy
https://www.readbyqxmd.com/read/27909446/functional-toxicogenomic-profiling-expands-insight-into-modulators-of-formaldehyde-toxicity-in-yeast
#17
Matthew North, Brandon D Gaytán, Carlos Romero, Vanessa Y De La Rosa, Alex Loguinov, Martyn T Smith, Luoping Zhang, Chris D Vulpe
Formaldehyde (FA) is a commercially important chemical with numerous and diverse uses. Accordingly, occupational and environmental exposure to FA is prevalent worldwide. Various adverse effects, including nasopharyngeal, sinonasal, and lymphohematopoietic cancers, have been linked to FA exposure, prompting designation of FA as a human carcinogen by U.S. and international scientific entities. Although the mechanism(s) of FA toxicity have been well studied, additional insight is needed in regard to the genetic requirements for FA tolerance...
2016: Frontiers in Genetics
https://www.readbyqxmd.com/read/27908934/gata6-promotes-hair-follicle-progenitor-cell-renewal-by-genome-maintenance-during-proliferation
#18
Alex B Wang, Ying V Zhang, Tudorita Tumbar
Cell proliferation is essential to rapid tissue growth and repair, but can result in replication-associated genome damage. Here, we implicate the transcription factor Gata6 in adult mouse hair follicle regeneration where it controls the renewal of rapidly proliferating epithelial (matrix) progenitors and hence the extent of production of terminally differentiated lineages. We find that Gata6 protects against DNA damage associated with proliferation, thus preventing cell cycle arrest and apoptosis. Furthermore, we show that in vivo Gata6 stimulates EDA-receptor signaling adaptor Edaradd level and NF-κB pathway activation, known to be important for DNA damage repair and stress response in general and for hair follicle growth in particular...
December 1, 2016: EMBO Journal
https://www.readbyqxmd.com/read/27908668/associations-between-urinary-biomarkers-of-oxidative-stress-and-air-pollutants-observed-in-a-randomized-crossover-exposure-to-steel-mill-emissions
#19
Guillaume Pelletier, Marc Rigden, Lisa Marie Kauri, Robin Shutt, Mamun Mahmud, Sabit Cakmak, Premkumari Kumarathasan, Errol M Thomson, Renaud Vincent, Gayle Broad, Ling Liu, Robert Dales
The effects of industrial air pollution on human health have not been as thoroughly investigated as those of urban air pollution which originates mostly from automotive transport. To better assess the health impacts of point sources of industrial air pollution, a randomized crossover exposure study was conducted. Sixty one young and healthy volunteers were randomly assigned to spend five consecutive eight-hour days near a steel mill or at a location five kilometres away. After a nine or sixteen-day washout period, volunteers spent another five consecutive days at the second site...
November 25, 2016: International Journal of Hygiene and Environmental Health
https://www.readbyqxmd.com/read/27908386/genetic-polymorphisms-in-19q13-3-genes-associated-with-alteration-of-repair-capacity-to-bpde-dna-adducts-in-primary-cultured-lymphocytes
#20
Mingyang Xiao, Sha Xiao, Tahar van der Straaten, Ping Xue, Guopei Zhang, Xiao Zheng, Qianye Zhang, Yuan Cai, Cuihong Jin, Jinghua Yang, Shengwen Wu, Guolian Zhu, Xiaobo Lu
Benzo[a]pyrene(B[a]P), and its ultimate metabolite Benzo[a]pyrene 7,8-diol 9,10-epoxide (BPDE), are classic DNA damaging carcinogens. DNA damage in cells caused by BPDE is normally repaired by Nucleotide Excision Repair (NER) and Base Excision Repair (BER). Genetic variations in NER and BER can change individual DNA repair capacity to DNA damage induced by BPDE. In the present study we determined the number of in vitro induced BPDE-DNA adducts in lymphocytes, to reflect individual susceptibility to Polycyclic aromatic hydrocarbons (PAHs)-induced carcinogenesis...
December 2016: Mutation Research
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