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Debadrita Bhattacharya, Disha Hiregange, Basuthkar J Rao
In eukaryotes, in response to replication stress, DNA damage response kinase, ATR is activated, whose signalling abrogation leads to cell lethality due to aberrant fork remodelling and excessive origin firing. Here we report that inhibition of ATR kinase activity specifically during replication stress recovery results in persistent ATR signalling, evidenced by the presence of ATR-dependent phosphorylation marks (gamma H2AX, pChk1 and pRad17) and delayed cell cycle re-entry. Further, such disruption of ATR signalling attenuation leads to double-strand breaks, fork collapse and thereby 'replication catastrophe'...
March 2018: Journal of Biosciences
Jianbin Lai, Jieming Jiang, Qian Wu, Ning Mao, Danlu Han, Huan Hu, Chengwei Yang
DNA damage occurs in all cells and can hinder chromosome stability and cell viability. Structural Maintenance of Chromosomes 5/6 (SMC5/6) is a protein complex that functions as an evolutionarily conserved chromosomal ATPase critical for repairing DNA double-strand breaks (DSBs). However, the mechanisms regulating this complex in plants are poorly understood. Here, we identified the transcriptional coactivator ALTERATION/DEFICIENCY IN ACTIVATION 2B (ADA2b) as an interactor of SMC5 in Arabidopsis thaliana. ADA2b is a conserved component of the Spt-Ada-Gcn5 acetyltransferase (SAGA) complex, which functions in transcriptional regulation...
February 20, 2018: Plant Physiology
Paula M De Angelis, Aasa R Schjølberg, Juliana B Hughes, Henrik S Huitfeldt, Solveig Norheim Andersen, Anne Carine Østvold
Background: The colon and rectum are continuously exposed to oxidative stress that generates reactive oxygen species, which are a major cause of DNA double-strand breaks (DSB). Furthermore, chronic inflammatory diseases such as ulcerative colitis (UC) are characterized by an excess of reactive nitrogen species that can also lead to DNA double-strand breakage and genomic instability. We investigated the expression of the nuclear casein kinase and cyclin-dependent kinase substrate 1 (NUCKS1) protein in UC and sporadic colorectal cancer (CRC) due to its involvement in both DNA double-strand break repair and inflammatory signaling...
February 15, 2018: Inflammatory Bowel Diseases
Akshaykumar A Nayak, Kamalesh Dattaram Mumbrekar, Satish Rao
In a scenario of accidental mass radiation exposure, transportation and analyzing samples may take its time resulting in loss of biomarker information over this period. The present study aims to use phosphatases inhibitors for longer retention of foci signals to adopt γ-H2AX as a biodosimetric biomarker for the management of early triage. Peripheral blood lymphocytes isolated from healthy individuals irradiated in vitro with X-rays, and γ-H2AX analysed using fluorescent microscopy and flow cytometric methods...
January 22, 2018: Journal of Radiological Protection: Official Journal of the Society for Radiological Protection
Brendan D Hare, Tina M Thornton, Mercedes Rincon, Borivoj Golijanin, S Bradley King, Diane M Jaworski, William A Falls
Recent reports demonstrate that DNA damage is induced, and rapidly repaired, in circuits activated by experience. Moreover, stress hormones are known to slow DNA repair, suggesting that prolonged stress may result in persistent DNA damage. Prolonged stress is known to negatively impact physical and mental health; however, DNA damage as a factor in stress pathology has only begun to be explored. Histone H2A-X phosphorylated at serine 139 (γH2AX) is a marker of DNA double strand breaks (DSB), a type of damage that may lead to cell death if unrepaired...
January 15, 2018: Neuroscience
Kalnisha Naidoo, Patty T Wai, Sarah L Maguire, Frances Daley, Syed Haider, Divya Kriplani, James Campbell, Hasan Mirza, Anita Grigoriadis, Andrew Tutt, Paul M Moseley, Tarek M A Abdel-Fatah, Stephen Yt Chan, Srinivasan Madhusudan, Emad A Rakha, Ian O Ellis, Christopher J Lord, Yinyin Yuan, Andrew R Green, Rachael Natrajan
Disruption of Cyclin Dependent Kinase 12 (CDK12) is known to lead to defects in DNA repair and sensitivity to platinum salts and poly(ADP-ribose) polymerase 1/2 inhibitors. However, CDK12 has also been proposed as an oncogene in breast cancer. We therefore aimed to assess the frequency and distribution of CDK12 protein expression by immunohistochemistry (IHC) in independent cohorts of breast cancer and correlate this with outcome and genomic status. We found that 21% of primary unselected breast cancers were CDK12 high, and 10...
November 13, 2017: Molecular Cancer Therapeutics
Karen Suárez-Larios, Ana-María Salazar-Martínez, Regina Montero-Montoya
A study was realized to ascertain whether eight selected pesticides would induce double strand breaks (DSB) in lymphocyte cultures and whether this damage would induce greater levels of proteins Rad51 participating in homologous recombination or of p-Ku80 participating in nonhomologous end joining. Only five pesticides were found to induce DSB of which only glyphosate and paraoxon induced a significant increase of p-Ku80 protein, indicating that nonhomologous end joining recombinational DNA repair system would be activated...
2017: Journal of Toxicology
Tae Ho Ryu, Jin Kyu Kim, Jeong-Il Kim, Jin-Hong Kim
Plants are used as representative reference biota for the biological assessment of environmental risks such as ionizing radiation due to their immobility. This study proposed a faster, more economical, and more effective method than conventional cytogenetic methods for the biological dosimetry of ionizing radiation in plants (phytodosimetry). We compared various dose-response curves for the radiation-induced DNA damage response (DDR) in Arabidopsis thaliana after relatively "low-dose" gamma irradiation (3, 6, 12, 24, and 48 Gy) below tens of Gy using comet (or single-cell gel electrophoresis), gamma-H2AX, and transcriptomic assays of seven DDR genes (AGO2, BRCA1, GRG, PARP1, RAD17, RAD51, and RPA1E) using quantitative real time PCR...
January 2018: Journal of Environmental Radioactivity
Tamer El-Sayed, Ashish S Patel, Jun S Cho, James A Kelly, Francesca E Ludwinski, Prakash Saha, Oliver T Lyons, Alberto Smith, Bijan Modarai
Background -Radiation exposure during fluoroscopically-guided interventions such as endovascular aortic repair (EVAR) is a growing concern for operators. This study aimed to measure DNA damage/repair markers in operators perfoming EVAR. Methods -Expression of the DNA damage/repair marker, gamma-H2AX (γ-H2AX) and DNA damage response (DDR) marker, phosphorylated ataxia telangiectasia mutated (pATM), were quantified in circulating lymphocytes in operators during the peri-operative period of endovascular (infra-renal [IEVAR], branched [BEVAR] and fenestrated [FEVAR]) and open aortic repair using flow cytometry...
October 20, 2017: Circulation
So-Ra Kim, Eun-Hee Kim
PURPOSE: Despite the high radioresistance of melanoma, unresectable lesions can be subjected to radiation treatment with the use of gold nanoparticles (AuNPs) as a dose-enhancing agent preferentially loaded on these lesions. The modality of single high-dose treatment has been investigated to confirm its therapeutic efficiency for AuNP-treated melanoma cells. This study explores the feasibility of utilizing AuNPs in fractionated radiation therapy of melanoma for further therapeutic gain...
October 16, 2017: International Journal of Radiation Biology
Vinay Jain, Divyalakshmi Saini, P R Vivek Kumar, G Jaikrishan, Birajalaxmi Das
High level natural radiation areas (HLNRA) of Kerala coastal strip (55km long and 0.5km wide) in southwest India exhibit wide variations in the level of background dose (< 1.0-45.0mGy/year) due to thorium deposits in the beach sand. The areas with ≤1.5mGy/year are considered as normal level natural radiation area (NLNRA), whereas areas with >1.5mGy/year are HLNRA. Individuals belonging to HLNRA were stratified into two groups, Low dose group (LDG: 1.51-5.0mGy/year) and high dose group (HDG: >5.0mGy/year)...
December 2017: Mutation Research
Magdalena Kowalska, Aneta Wegierek-Ciuk, Kamil Brzoska, Maria Wojewodzka, Sylwia Meczynska-Wielgosz, Joanna Gromadzka-Ostrowska, Remigiusz Mruk, Johan Øvrevik, Marcin Kruszewski, Anna Lankoff
Epidemiological data indicate that exposure to diesel exhaust particles (DEPs) from traffic emissions is associated with higher risk of morbidity and mortality related to cardiovascular and pulmonary diseases, accelerated progression of atherosclerotic plaques, and possible lung cancer. While the impact of DEPs from combustion of fossil diesel fuel on human health has been extensively studied, current knowledge of DEPs from combustion of biofuels provides limited and inconsistent information about its mutagenicity and genotoxicity, as well as possible adverse health risks...
November 2017: Environmental Science and Pollution Research International
Shigeaki Sunada, Hirokazu Hirakawa, Akira Fujimori, Mitsuru Uesaka, Ryuichi Okayasu
High-linear energy transfer (LET) heavy ions cause higher therapeutic effects than low-LET radiation due to lower dependency on oxygen concentration in tumor cell killing. The lethality after irradiation largely depends on DNA double-strand breaks (DSBs), however the detailed LET dependency for DSB induction under oxic and hypoxic conditions has not been reported. Therefore, we evaluated the oxygen enhancement ratio (OER) of heavy ion-induced DSB induction using a highly-optimized flow cytometry-based method of γ-H2AX detection...
November 2017: Radiation Research
Jerome M Hershman, Bryan France, Kevin Hon, Robert Damoiseaux
Genotoxicity is thought to be the cause of many cancers. Genotoxicity due to environmental toxins may be partly responsible for the dramatic increase in the incidence of papillary thyroid cancer over the past two decades. Here, we present a fully automatable assay platform that directly quantifies the phosphorylation of nuclear histone gamma H2AX (γH2AX), a specific cellular marker for DNA double strand breaks (DSBs) via immunohistochemistry and laser scanning cytometry. It multiplexes γH2AX with total cell number measured as propidium iodide and calculates the percentage of cells with DSBs...
August 2017: Environmental and Molecular Mutagenesis
Hiroshi Doi, Seiji Matsumoto, Soichi Odawara, Toshiyuki Shikata, Kazuhiro Kitajima, Masao Tanooka, Yasuhiro Takada, Tohru Tsujimura, Norihiko Kamikonya, Shozo Hirota
Pravastatin is an inhibitor of 3-hydroxy-3-methyl- glutaryl-coenzyme A reductase that has been reported to have therapeutic applications in a range of inflammatory conditions. The aim of the present study was to assess the radioprotective effects of pravastatin in an experimental animal model. Mice were divided into two groups: The control group received ionizing radiation with no prior medication, while the pravastatin group received pravastatin prior to ionizing radiation. Pravastatin was administered orally at 30 mg/kg body weight in drinking water at 24 and 4 h before irradiation...
May 2017: Experimental and Therapeutic Medicine
B Gagnaire, C Adam-Guillermin, A Festarini, I Cavalié, C Della-Vedova, C Shultz, S B Kim, H Ikert, C Dubois, S Walsh, F Farrow, D Beaton, E Tan, K Wen, M Stuart
Aquatic ecosystems are chronically exposed to radionuclides as well as other pollutants. Increased concentrations of pollutants in aquatic environments can present a risk to exposed organisms, including fish. The goal of this study was to characterize the effects of tritium, in the context of natural environments, on the health of fathead minnow, Pimephales promelas. Fish were exposed to tritium (activity concentrations ranging from 2 to 23,000Bq/L) and also to various concentrations of several metals to replicate multiple-stressor environments...
December 1, 2017: Science of the Total Environment
Jing Liu, Yong Zhao, Wei Ge, Pengfei Zhang, Xinqi Liu, Weidong Zhang, Yanan Hao, Shuai Yu, Lan Li, Meiqiang Chu, Lingjiang Min, Hongfu Zhang, Wei Shen
The impacts of zinc oxide nanoparticles on embryonic development following oocyte stage exposure are unknown and the underlying mechanisms are sparsely understood. In the current investigation, intact nanoparticles were detected in ovarian tissue in vivo and cultured cells in vitro under zinc oxide nanoparticles treatment. Zinc oxide nanoparticles exposure during the oocyte stage inhibited embryonic development. Notably, in vitro culture data closely matched in vivo embryonic data, in that the impairments caused by Zinc oxide nanoparticles treatment passed through cell generations; and both gamma-H2AX and NF-kappaB pathways were involved in zinc oxide nanoparticles caused embryo-toxicity...
June 27, 2017: Oncotarget
Dorota Piekna-Przybylska, Gaurav Sharma, Sanjay B Maggirwar, Robert A Bambara
Viruses can interact with host cell molecules responsible for the recognition and repair of DNA lesions, resulting in dysfunctional DNA damage response (DDR). Cells with inefficient DDR are more vulnerable to therapeutic approaches that target DDR, thereby raising DNA damage to a threshold that triggers apoptosis. Here, we demonstrate that 2 Jurkat-derived cell lines with incorporated silent HIV-1 provirus show increases in DDR signaling that responds to formation of double strand DNA breaks (DSBs). We found that phosphorylation of histone H2AX on Ser139 (gamma-H2AX), a biomarker of DSBs, and phosphorylation of ATM at Ser1981, Chk2 at Thr68, and p53 at Ser15, part of signaling pathways associated with DSBs, are elevated in these cells...
May 19, 2017: Cell Cycle
Viktoria-Varvara Palla, Georgios Karaolanis, Ioannis Katafigiotis, Ioannis Anastasiou, Paul Patapis, Dimitrios Dimitroulis, Despoina Perrea
Double-strand breaks are among the first procedures taking place in cancer formation and progression as a result of endogenic and exogenic factors. The histone variant H2AX undergoes phosphorylation at serine 139 due to double-strand breaks, and the gamma-H2AX is formatted as a result of genomic instability. The detection of gamma-H2AX can potentially serve as a biomarker for transformation of normal tissue to premalignant and consequently to malignant tissues. gamma-H2AX has already been investigated in a variety of cancer types, including breast, lung, colon, cervix, and ovary cancers...
March 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Tiziana Squillaro, Ivana Antonucci, Nicola Alessio, Anna Esposito, Marilena Cipollaro, Mariarosa Anna Beatrice Melone, Gianfranco Peluso, Liborio Stuppia, Umberto Galderisi
Lysosomal storage disorders (LDS) comprise a group of rare multisystemic diseases resulting from inherited gene mutations that impair lysosomal homeostasis. The most common LSDs, Gaucher disease (GD), and Fabry disease (FD) are caused by deficiencies in the lysosomal glucocerebrosidase (GBA) and alpha-galactosidase A (GLA) enzymes, respectively. Given the systemic nature of enzyme deficiency, we hypothesized that the stem cell compartment of GD and FD patients might be also affected. Among stem cells, mesenchymal stem cells (MSCs) are a commonly investigated population given their role in hematopoiesis and the homeostatic maintenance of many organs and tissues...
December 2017: Journal of Cellular Physiology
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