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DNA DAMAGE AND REPAIR

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https://www.readbyqxmd.com/read/29785231/advantages-of-evaluating-%C3%AE-h2ax-induction-in-non-clinical-drug-development
#1
REVIEW
Shigeki Motoyama, Akira Takeiri, Kenji Tanaka, Asako Harada, Kaori Matsuzaki, Junko Taketo, Saori Matsuo, Etsuko Fujii, Masayuki Mishima
γH2AX, the phosphorylated form of a histone variant H2AX at Ser 139, is already widely used as a biomarker to research the fundamental biology of DNA damage and repair and to assess the risk of environmental chemicals, pollutants, radiation, and so on. It is also beginning to be used in the early non-clinical stage of pharmaceutical drug development as an in vitro tool for screening and for mechanistic studies on genotoxicity. Here, we review the available information on γH2AX-based test systems that can be used to develop drugs and present our own experience of practically applying these systems during the non-clinical phase of drug development...
2018: Genes and Environment: the Official Journal of the Japanese Environmental Mutagen Society
https://www.readbyqxmd.com/read/29783721/azd1775-increases-sensitivity-to-olaparib-and-gemcitabine-in-cancer-cells-with-p53-mutations
#2
Xiangbing Meng, Jianling Bi, Yujun Li, Shujie Yang, Yuping Zhang, Mary Li, Haitao Liu, Yiyang Li, Megan E Mcdonald, Kristina W Thiel, Kuo-Kuang Wen, Xinhao Wang, Meng Wu, Kimberly K Leslie
Tumor suppressor p53 is responsible for enforcing cell cycle checkpoints at G1/S and G2/M in response to DNA damage, thereby allowing both normal and tumor cells to repair DNA before entering S and M. However, tumor cells with absent or mutated p53 are able to activate alternative signaling pathways that maintain the G2/M checkpoint, which becomes uniquely critical for the survival of such tumor cells. We hypothesized that abrogation of the G2 checkpoint might preferentially sensitize p53-defective tumor cells to DNA-damaging agents and spare normal cells with intact p53 function...
May 19, 2018: Cancers
https://www.readbyqxmd.com/read/29780750/the-luxs-ai-2-quorum-sensing-system-of-streptococcus-pneumoniae-is-required-to-cause-disease-and-to-regulate-virulence-and-metabolism-related-genes-in-a-rat-model-of-middle-ear-infection
#3
Mukesh K Yadav, Jorge E Vidal, Yoon Y Go, Shin H Kim, Sung-Won Chae, Jae-Jun Song
Objective: Streptococcus pneumoniae colonizes the nasopharynx of children, and from nasopharynx it could migrate to the middle ear and causes acute otitis media (AOM). During colonization and AOM, the pneumococcus forms biofilms. In vitro biofilm formation requires a functional LuxS/AI-2 quorum-sensing system. We investigated the role of LuxS/AI-2 signaling in pneumococcal middle ear infection, and identified the genes that are regulated by LuxS/AI-2 during pneumococcal biofilm formation. Methods: Streptococcus pneumoniae D39 wild-type and an isogenic D39Δ luxS strain were utilized to evaluate in vitro biofilm formation, and in vivo colonization and epithelial damage using a microtiter plate assay and a rat model of pneumococcal middle ear infection, respectively...
2018: Frontiers in Cellular and Infection Microbiology
https://www.readbyqxmd.com/read/29780501/a-bi-terminal-protein-ligation-strategy-to-probe-chromatin-structure-during-dna-damage
#4
Sinan Kilic, Iuliia Boichenko, Carolin C Lechner, Beat Fierz
The cellular response to DNA damage results in a signaling cascade that primes chromatin for repair. Combinatorial post-translational modifications (PTMs) play an important role in this process by altering the physical properties of chromatin and recruiting downstream factors. One key signal integrator is the histone variant H2A.X, which is phosphorylated at a C-terminal serine (S139ph), and ubiquitylated within its N-terminal tail at lysines 13 and 15 (K13/15ub). How these PTMs directly impact chromatin structure and thereby facilitate DNA repair is not well understood...
April 21, 2018: Chemical Science
https://www.readbyqxmd.com/read/29780063/the-effect-of-ozone-on-colonic-epithelial-cells
#5
Hidetomo Himuro
Due to its strong oxidation activity, ozone has been well known to kill bacteria and exert toxic effects on human tissues. At the same time, ozone is being used for the treatment of diseases such as inflammatory bowel disease in some European countries. However, the use of ozone for therapeutic purposes, despite its strong toxic effects, remains largely unexplored. Interestingly, we found that intrarectal administration of ozone gas induced transient colonic epithelial cell damage characterized by the impairment of cell survival pathways involved in DNA replication, cell cycle, and mismatch repair...
May 21, 2018: Kurume Medical Journal
https://www.readbyqxmd.com/read/29775409/transactivation-domain-of-p53-regulates-dna-repair-and-integrity-in-human-ips-cells
#6
Ramaswamy Kannappan, Saidulu Mattapally, Pooja A Wagle, Jianyi Zhang
The role of p53 transactivation domain (p53-TAD), a multifunctional and dynamic domain, on DNA repair and retaining DNA integrity in human iPS cells has never been studied. p53-TAD was knocked out in iPS cells using CRISPR/Cas9 and was confirmed by DNA sequencing. p53-TAD KO cells were characterized by: accelerated proliferation, decreased population doubling time, and unaltered Bcl2, BBC3, IGF1R, Bax and altered Mdm2, p21, and PIDD transcripts expression. In p53-TAD KO cells p53 regulated DNA repair proteins XPA, DNA polH and DDB2 expression were found to be reduced compared to p53-WT cells...
May 18, 2018: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/29775397/receptor-tyrosine-kinase-signaling-in-cancer-radiotherapy-and-its-targeting-for-tumor-radiosensitization
#7
Poushali Bhattacharya, Neena G Shetake, Badri N Pandey, Amit Kumar
PURPOSE: One of the most important implications of 'Radiation Biology' research is to improve cancer radiotherapy with minimum side effects. In this regard, combination of chemotherapy with radiation has significantly improved tumor control as well as overall survival in a variety of cancers. However, this has been achieved at the cost of significant normal tissue toxicity, due to the lack of specificity of chemotherapy. Membrane-localized receptor tyrosine kinases (RTKs) have been found to play a driving role in various hallmarks of cancer...
May 18, 2018: International Journal of Radiation Biology
https://www.readbyqxmd.com/read/29775010/-molecular-mechanisms-of-chemoresistance-in-head-and-neck-squamous-cell-carcinoma
#8
REVIEW
Y X Zhao, Z F Sun
Head and neck squamous cell carcinoma (HNSCC) is an aggressive neoplasm with the properties of local recurrence and distant metastasis. Currently, cisplatin-based chemotherapy or concurrent radiochemotherapy is still the first choice or the treatment of advanced HNSCC. However, chemoresistance greatly limited the effectiveness of chemotherapy. Therefore, illustrating the mechanisms of chemoresistance is very important for the treatment of HNSCC. In this article, we summarize the molecular mechanisms of chemoresitance in HNSCC from the perspective of drug efflux, apoptosis, DNA damage and repair, epithelial mesenchymal transition and autophagy...
June 5, 2017: Journal of Clinical Otorhinolaryngology, Head, and Neck Surgery
https://www.readbyqxmd.com/read/29774413/alterations-in-histone-acetylation-following-exposure-to-60-co-%C3%AE-rays-and-their-relationship-with-chromosome-damage-in-human-lymphoblastoid-cells
#9
Xue-Lei Tian, Xue Lu, Jiang-Bin Feng, Tian-Jing Cai, Shuang Li, Mei Tian, Qing-Jie Liu
Chromosome damage is related to DNA damage and erroneous repair. It can cause cell dysfunction and ultimately induce carcinogenesis. Histone acetylation is crucial for regulating chromatin structure and DNA damage repair. Ionizing radiation (IR) can alter histone acetylation. However, variations in histone acetylation in response to IR exposure and the relationship between histone acetylation and IR-induced chromosome damage remains unclear. Hence, this study investigated the variation in the total acetylation levels of H3 and H4 in human lymphocytes exposed to 0-2 Gy 60 Co γ-rays...
May 17, 2018: Radiation and Environmental Biophysics
https://www.readbyqxmd.com/read/29773766/impact-of-the-ser326cys-polymorphism-of-the-ogg1-gene-on-the-level-of-oxidative-dna-damage-in-patients-with-colorectal-cancer
#10
Jacek Kabzinski, Anna Walczak, Adam Dziki, Michał Mik, Ireneusz Majsterek
As a result of reactive oxygen species operation, cell damage occurs in both cellular organelles and molecules, including DNA. Oxidative damage within the genetic material can lead to accumulation of mutations and consequently to cancer transformation. OGG1 glycosylase, a component of the Base Excision Repair (BER) system, is one of the enzymes that prevents excessive accumulation of 8-oxoguanine (8-oxG), the most common compound formed by oxidative DNA damage. In case of structural changes of OGG1 resulting from polymorphic variants, we can observe a significant increase in the concentration of 8-oxG...
April 30, 2018: Polski Przeglad Chirurgiczny
https://www.readbyqxmd.com/read/29773007/cell-proliferation-and-dna-repair-ability-of-ganoderma-neo-japonicum-agaricomycetes-an-indigenous-medicinal-mushroom-from-malaysia
#11
Wee Cheat Tan, Umah Rani Kuppusamy, Chia Wei Phan, Vikineswary Sabaratnam
Ganoderma neo-japonicum is an annual polypore that grows on decaying bamboo in the forests of Malaysia. The indigenous Temuan tribe uses this species as a medicinal mushroom to cure fever and epilepsy and to improve body strength. The potential use of G. neo-japonicum in genoprotection and DNA repair was established using a single-cell gel electrophoresis (comet) assay. The effects of the ethanol and hot aqueous extracts from wild and cultivated basidiocarps, solid substrate-fermented (SSF) wheat grains, and mycelia via submerged culture on H2O2-damaged murine RAW264...
2018: International Journal of Medicinal Mushrooms
https://www.readbyqxmd.com/read/29770165/targeting-oxidatively-induced-dna-damage-response-in-cancer-opportunities-for-novel-cancer-therapies
#12
REVIEW
Pierpaola Davalli, Gaetano Marverti, Angela Lauriola, Domenico D'Arca
Cancer is a death cause in economically developed countries that results growing also in developing countries. Improved outcome through targeted interventions faces the scarce selectivity of the therapies and the development of resistance to them that compromise the therapeutic effects. Genomic instability is a typical cancer hallmark due to DNA damage by genetic mutations, reactive oxygen and nitrogen species, ionizing radiation, and chemotherapeutic agents. DNA lesions can induce and/or support various diseases, including cancer...
2018: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/29769404/dna-activates-the-nse2-mms21-sumo-e3-ligase-in-the-smc5-6-complex
#13
Nathalia Varejão, Eva Ibars, Jara Lascorz, Neus Colomina, Jordi Torres-Rosell, David Reverter
Modification of chromosomal proteins by conjugation to SUMO is a key step to cope with DNA damage and to maintain the integrity of the genome. The recruitment of SUMO E3 ligases to chromatin may represent one layer of control on protein sumoylation. However, we currently do not understand how cells upregulate the activity of E3 ligases on chromatin. Here we show that the Nse2 SUMO E3 in the Smc5/6 complex, a critical player during recombinational DNA repair, is directly stimulated by binding to DNA Activation of sumoylation requires the electrostatic interaction between DNA and a positively charged patch in the ARM domain of Smc5, which acts as a DNA sensor that subsequently promotes a stimulatory activation of the E3 activity in Nse2...
May 16, 2018: EMBO Journal
https://www.readbyqxmd.com/read/29769345/the-major-tegument-protein-of-bovine-herpesvirus-1-vp8-interacts-with-dna-damage-response-proteins-and-induces-apoptosis
#14
Sharmin Afroz, Ravendra Garg, Michel Fodje, Sylvia van Drunen Littel-van den Hurk
VP8, the UL47 gene product in bovine herpes virus-1 (BoHV-1), is a major tegument protein, essential for virus replication in vivo The major DNA damage response protein, ataxia telangiectasia mutated (ATM), phosphorylates Nijmegen breakage syndrome (NBS1) and structural maintenance of chromosome-1 (SMC1) proteins during the DNA damage response. VP8 was found to interact with ATM and NBS1 during transfection and BoHV-1 infection. However, VP8 did not interfere with phosphorylation of ATM in transfected or BoHV-1-infected cells...
May 16, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29768722/genoprotective-effect-of-phyllanthus-orbicularis-extract-against-uva-uvb-and-solar-radiation
#15
Marioly Vernhes Tamayo, André Passaglia Schuch, Teiti Yagura, Luis Baly Gil, Carlos Frederico Martins Menck, Angel Sánchez-Lamar
One approach to protect the human skin against harmful effects of solar ultraviolet (UV) radiation is to use natural products as photoprotectors. In this work, the extract from specie Phyllanthus orbicularis K was evaluated as a protective agent against the photodamage by UVB, UVA artificial lamps and environmental sunlight exposure. The plasmid DNA solutions were exposed to radiations using the DNA-dosimeter system in presence of plant extract. The DNA repair enzymes, E. coli Formamidopyrimidine-DNA glycosylase (Fpg) and T4 bacteriophage endonuclease V (T4-endo V), were employed to discriminate oxidized DNA damage and cyclobutane pyrimidine dimers (CPD) respectively...
May 16, 2018: Photochemistry and Photobiology
https://www.readbyqxmd.com/read/29768183/ndrg1-disruption-alleviates-cisplatin-sodium-glycididazole-induced-dna-damage-response-and-apoptosis-in-ercc1-defective-lung-cancer-cells
#16
Lang He, Kang Liu, Xiaoshan Wang, Hong Chen, Jin Zhou, Xun Wu, Tao Liu, Yongxue Yang, Xuemei Yang, Dandan Cui, Guiqin Song, Jianguo Lei, Jun Wang
BACKGROUND: Resistance to platinum-based chemotherapy becomes a major obstacle in lung cancer treatment. Compensatory activation of nucleotide excision repair (NER) pathway is the major mechanism accounting for cisplatin-resistance. We aimed at identifying additional regulators in NER-mediated chemoresistance in a hypoxic setting induced by sodium glycididazole (CMNa)-sensitized cisplatin chemotherapy of non-small cell lung cancer (NSCLC). METHODS: We performed an RNA-sequencing (RNA-Seq) analysis to identify the genes whose expression had been differentially regulated in NER-deficient cells that had been treated by cisplatin/CMNa...
May 13, 2018: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/29767233/potential-role-of-cyclin-f-mrna-expression-in-the-survival-of-skin-melanoma-patients-comprehensive-analysis-of-the-pathways-altered-due-to-cyclin-f-upregulation
#17
Maciej Gagat, Adrian Krajewski, Dariusz Grzanka, Alina Grzanka
Cyclin F is a part of the Skp, Cullin, F-box containing ligase complex. The activity of cyclin F includes cell cycle control, centrosome duplication and response to DNA damage. The cyclin F expression pattern is very similar to cyclin A, but cyclin F is an orphan cyclin without its cyclin-dependent kinase partner. There is little evidence concerning the role of cyclin F in cancer. In the present study, for the first time, we present analysis from The Cancer Genome Atlas (TCGA) data in the context of expression of cyclin F mRNA in melanoma patients...
May 16, 2018: Oncology Reports
https://www.readbyqxmd.com/read/29765508/mir-200a-modulates-the-expression-of-the-dna-repair-protein-ogg1-playing-a-role-in-aging-of-primary-human-keratinocytes
#18
Lavinia Tinaburri, Mariarosaria D'Errico, Sara Sileno, Riccardo Maurelli, Paolo Degan, Alessandra Magenta, Elena Dellambra
Oxidative DNA damage accumulation may induce cellular senescence. Notably, senescent cells accumulate in aged tissues and are present at the sites of age-related pathologies. Although the signaling of DNA strand breaks has been extensively studied, the role of oxidative base lesions has not fully investigated in primary human keratinocyte aging. In this study, we show that primary human keratinocytes from elderly donors are characterized by a significant accumulation of the oxidative base lesion 8-OH-dG, impairment of oxidative DNA repair, and increase of miR-200a levels...
2018: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/29763378/characterization-of-thermally-activated-metalloenediyne-cytotoxicity-in-human-melanoma-cells
#19
Eric J Keller, Meghan Porter, Joy E Garrett, Meredith Varie, Haiyan Wang, Karen E Pollok, John J Turchi, Jeffrey M Zaleski, Joseph R Dynlacht
Enediynes are a highly cytotoxic class of compounds. However, metallation of these compounds may modulate their activation, and thus their cytotoxicity. We previously demonstrated that cytotoxicity of two different metalloenediynes, including (Z)-N,N'-bis[1-pyridyl-2-yl-meth-(E)-ylidene]octa-4-ene-2,6-diyne-1,8-diamine] (PyED), is potentiated when the compounds are administered to HeLa cells during hyperthermia treatment at concentrations that are minimally or not cytotoxic at 37°C. In this study, we further characterized the concentration, time and temperature dependence of cytotoxicity of PyED on human U-1 melanoma cells...
May 15, 2018: Radiation Research
https://www.readbyqxmd.com/read/29762762/coulomb-and-ch-%C3%AF-interactions-in-6-4-photolyase-dna-complex-dominate-dna-binding-and-repair-abilities
#20
Yuma Terai, Ryuma Sato, Takahiro Yumiba, Ryuhei Harada, Kohei Shimizu, Tatsuya Toga, Tomoko Ishikawa-Fujiwara, Takeshi Todo, Shigenori Iwai, Yasuteru Shigeta, Junpei Yamamoto
(6-4) Photolyases ((6-4)PLs) are flavoenzymes that repair the carcinogenic UV-induced DNA damage, pyrimidine(6-4)pyrimidone photoproducts ((6-4)PPs), in a light-dependent manner. Although the reaction mechanism of DNA photorepair by (6-4)PLs has been intensively investigated, the molecular mechanism of the lesion recognition remains obscure. We show that a well-conserved arginine residue in Xenopus laevis (6-4)PL (Xl64) participates in DNA binding, through Coulomb and CH-π interactions. Fragment molecular orbital calculations estimated attractive interaction energies of -80-100 kcal mol-1 for the Coulomb interaction and -6 kcal mol-1 for the CH-π interaction, and the loss of either of them significantly reduced the affinity for (6-4)PP-containing oligonucleotides, as well as the quantum yield of DNA photorepair...
May 14, 2018: Nucleic Acids Research
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