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Jolein Mijnes, Jürgen Veeck, Nadine T Gaisa, Eduard Burghardt, Tim C de Ruijter, Sonja Gostek, Edgar Dahl, David Pfister, Sebastian C Schmid, Ruth Knüchel, Michael Rose
Background: Genome-wide studies identified pan-cancer genes and shared biological networks affected by epigenetic dysregulation among diverse tumor entities. Here, we systematically screened for hypermethylation of DNA damage repair (DDR) genes in a comprehensive candidate-approach and exemplarily identify and validate candidate DDR genes as targets of epigenetic inactivation unique to bladder cancer (BLCA), which may serve as non-invasive biomarkers. Methods: Genome-wide DNA methylation datasets (2755 CpG probes of n = 7819 tumor and n = 659 normal samples) of the TCGA network covering 32 tumor entities were analyzed in silico for 177 DDR genes...
2018: Clinical Epigenetics
Bryndon J Oleson, Aaron Naatz, Sarah C Proudfoot, Chay Teng Yeo, John A Corbett
Nitric oxide is produced at micromolar levels by pancreatic β-cells during exposure to proinflammatory cytokines. While classically viewed as damaging, nitric oxide also activates pathways that promote β-cell survival. We have shown that nitric oxide, in a cell type selective manner, inhibits the DNA damage response (DDR) and, in doing so, protects β-cells from DNA damage-induced apoptosis. This study explores potential mechanisms by which nitric oxide inhibits DDR signaling. We show that inhibition of DDR signaling (measured by γH2AX formation and the phosphorylation of KAP1) is selective for nitric oxide, as other forms of reactive oxygen/nitrogen species do not impair DDR signaling...
February 14, 2018: Diabetes
Xiangduo Kong, Gladys M S Cruz, Bárbara A Silva, Nicole M Wakida, Nima Khatibzadeh, Michael W Berns, Kyoko Yokomori
DNA damage induces specific signaling and repair responses in the cell, which is critical for protection of genome integrity. Laser microirradiation became a valuable experimental tool to investigate the DNA damage response (DDR) in vivo. It allows real-time high-resolution single-cell analysis of macromolecular dynamics in response to laser-induced damage confined to a submicrometer region in the cell nucleus. However, various laser conditions have been used without appreciation of differences in the types of damage induced...
January 31, 2018: Journal of Visualized Experiments: JoVE
Giorgio Marchesini, Davide Mottaran, Barbara Contiero, Eliana Schiavon, Severino Segato, Elisabetta Garbin, Sandro Tenti, Igino Andrighetto
The aim of this study was to measure the level of activity and rumination in young bulls and to assess whether these data can be used as indicators of health status and average daily weight gain (ADG). Two groups of animals (period 1: n=108 animals; period 2: n=106 animals) were fitted with sensors to measure daily activity and rumination, were weighed on arrival and at the end of the trial (70 days) and were checked twice daily to verify their health condition. Any clinical signs and therapies were recorded...
January 2018: Veterinary Journal
J Luis Espinoza, Mika Minami
The human genome is constantly exposed to exogenous and endogenous DNA damaging factors that frequently cause DNA damages. Unless repaired, damaged DNA can result in deleterious mutations capable of causing malignant transformation. Accordingly, cells have developed an advanced and effective surveillance system, the DNA damage response (DDR) pathway, which maintains genetic integrity. In addition to well-defined outcomes, such as cell cycle arrest, apoptosis, and senescence, another consequence of DDR activation is the induction of natural killer group 2 member D ligands (NKG2D-Ls) on the surface of stressed cells...
2018: Frontiers in Immunology
Adam Omelianchuk
Although much has been written on the dead-donor rule (DDR) in the last twenty-five years, scant attention has been paid to how it should be formulated, what its rationale is, and why it was accepted. The DDR can be formulated in terms of either a Don't Kill rule or a Death Requirement, the former being historically rooted in absolutist ethics and the latter in a prudential policy aimed at securing trust in the transplant enterprise. I contend that the moral core of the rule is the Don't Kill rule, not the Death Requirement...
February 6, 2018: Theoretical Medicine and Bioethics
Irina O Vassilieva, Galina F Reshetnikova, Alla N Shatrova, Nataliya V Tsupkina, Marianna V Kharchenko, Larisa L Alekseenko, Nikolay N Nikolsky, Elena B Burova
Accumulating evidence suggests that the senescence-messaging secretome (SMS) factors released by senescent cells play a key role in cellular senescence and physiological aging. Phenomenon of the senescence induction in human endometrium-derived mesenchymal stem cells (MESCs) in response to SMS factors has not yet been described. In present study, we examine a hypothesis whether the conditioned medium from senescent cells (CM-old) may promote premature senescence of young MESCs. In this case, we assume that SMS factors, containing in CM-old are capable to trigger senescence mechanism in a paracrine manner...
January 31, 2018: Biochemical and Biophysical Research Communications
Qingyuan Yang, Wanrun Lin, Zhiwei Liu, Jiabei Zhu, Nan Huang, Zhongqi Cui, Zeping Han, Qiuhui Pan, Ajay Goel, Fenyong Sun
Esophageal squamous cell carcinoma (ESCC) is the most popular pathology of esophageal cancer (EC) in China, especially in Henan province, mid-east of China. Presently, targeting DNA damage repair (DDR) factors is a promising approach for cancer therapy. Our group has been focusing on exploring the DDR factors overexpressed in ESCC tissues to provide potential targets for therapies for many years. RAP80/UIMC1 (ubiquitin interaction motif containing 1), one of those DDR factors we tested, was highly overexpressed in ESCC tissues compared with adjacent normal tissues...
February 2, 2018: Cell Death & Disease
Fade Gong, Kyle M Miller
Our genetic information is organized into chromatin, which consists of histones and proteins involved in regulating DNA compaction, accessibility and function. Chromatin is decorated by histone modifications, which provide signals that coordinate DNA-based processes including transcription and DNA damage response (DDR) pathways. A major signal involved in these processes is acetylation, which when attached to lysines within proteins, including histones, can be recognized and read by bromodomain-containing proteins...
February 2, 2018: Cell Cycle
Laetitia Maestroni, Vincent Géli, Stéphane Coulon
Telomere maintenance mechanism is poorly studied in quiescence, a reversible non-proliferative state. We previously described in fission yeast a new mode of repair of telomeres named STEEx, that specifically operates in post-mitotic cells harboring eroded telomeres. This mechanism, promoted by transcription-induced telomeric recombination, prevents cells to exit properly from quiescence, suggesting that STEEx act as an anti-proliferative barrier. Here, we further showed that STEEx are genetically controlled by the Tel1ATM- and Rad3ATR- dependent DDR pathways...
February 1, 2018: Current Genetics
Emil Mladenov, Fanghua Li, Lihua Zhang, Holger Klammer, George Iliakis
PURPOSE: A well-known phenomenon in the field of radiation biology is that cells exposed to ionizing radiation (IR) (targeted cells) can induce in non-irradiated (non-targeted), bystander cells effects reminiscent of DNA damage responses (DDR) normally expected, exclusively in targeted cells. These phenomena are collectively referred to as radiation-induced bystander effects (RIBE) and have different manifestations depending on the endpoint studied. Although it is now recognized that RIBE reflect to a considerable extent communication by the targeted cells to undamaged cells of their damaged status, the molecular underpinnings of this communication and its significance for the organism are only partly understood...
January 29, 2018: International Journal of Radiation Biology
Pierre Bady, Sebastian Kurscheid, Mauro Delorenzi, Thierry Gorlia, Martin J van den Bent, Khê Hoang-Xuan, Élodie Vauléon, Anja Gijtenbeek, Roelien Enting, Brian Thiessen, Olivier Chinot, Frédéric Dhermain, Alba A Brandes, Jaap C Reijneveld, Christine Marosi, Martin J B Taphoorn, Wolfgang Wick, Andreas von Deimling, Pim French, Roger Stupp, Brigitta G Baumert, Monika E Hegi
The optimal treatment for patients with low-grade glioma (LGG) WHO grade II remains controversial. Overall survival ranges from 2 to over 15 years depending on molecular and clinical factors. Hence, risk-adjusted treatments are required for optimizing outcome and quality of life. We aim at identifying mechanisms and associated molecular markers predictive for benefit from radiotherapy (RT) or temozolomide (TMZ) in LGG patients treated in the randomized phase III trial EORTC 22033. As candidate biomarkers for these genotoxic treatments, we considered the DNA methylome of 410 DNA damage response (DDR) genes...
January 24, 2018: Acta Neuropathologica
Marcel Naumann, Arun Pal, Anand Goswami, Xenia Lojewski, Julia Japtok, Anne Vehlow, Maximilian Naujock, René Günther, Mengmeng Jin, Nancy Stanslowsky, Peter Reinhardt, Jared Sterneckert, Marie Frickenhaus, Francisco Pan-Montojo, Erik Storkebaum, Ina Poser, Axel Freischmidt, Jochen H Weishaupt, Karlheinz Holzmann, Dirk Troost, Albert C Ludolph, Tobias M Boeckers, Stefan Liebau, Susanne Petri, Nils Cordes, Anthony A Hyman, Florian Wegner, Stephan W Grill, Joachim Weis, Alexander Storch, Andreas Hermann
Amyotrophic lateral sclerosis (ALS) is the most frequent motor neuron disease. Cytoplasmic fused in sarcoma (FUS) aggregates are pathological hallmarks of FUS-ALS. Proper shuttling between the nucleus and cytoplasm is essential for physiological cell function. However, the initial event in the pathophysiology of FUS-ALS remains enigmatic. Using human induced pluripotent stem cell (hiPSCs)-derived motor neurons (MNs), we show that impairment of poly(ADP-ribose) polymerase (PARP)-dependent DNA damage response (DDR) signaling due to mutations in the FUS nuclear localization sequence (NLS) induces additional cytoplasmic FUS mislocalization which in turn results in neurodegeneration and FUS aggregate formation...
January 23, 2018: Nature Communications
Ritesh Srivastava, Amie M Traylor, Changzhao Li, Wenguang Feng, Lingling Guo, Veena B Antony, Trenton R Schoeb, Anupam Agarwal, Mohammad Athar
Lewisite (2-chlorovinyldichloroarsine) is an organic and arsenical chemical warfare agent which was developed and weaponized during World Wars I/II. Stockpiles of lewisite still exist in many parts of the world and pose potential environmental and human health threat. Exposure to lewisite and similar chemicals causes intense cutaneous inflammatory response. However, morbidity and mortality in the exposed population is not only due to cutaneous damage but is also a result of systemic injury. Here, we provide data delineating the pathogenesis of acute kidney injury (AKI) following cutaneous exposure to lewisite and its analogue phenylarsine oxide (PAO) in a murine model...
January 17, 2018: American Journal of Physiology. Renal Physiology
Yunfeng Lin, Liping Bai, Steven Cupello, Md Akram Hossain, Bradley Deem, Melissa McLeod, Jude Raj, Shan Yan
As the most common type of DNA damage, DNA single-strand breaks (SSBs) are primarily repaired by the SSB repair mechanism. If not repaired properly or promptly, unrepaired SSBs lead to genome stability and have been implicated in cancer and neurodegenerative diseases. However, it remains unknown how unrepaired SSBs are recognized by DNA damage response (DDR) pathway, largely because of the lack of a feasible experimental system. Here, we demonstrate evidence showing that an ATR-dependent checkpoint signaling is activated by a defined plasmid-based site-specific SSB structure in Xenopus HSS (high-speed supernatant) system...
January 19, 2018: Nucleic Acids Research
Renata Alleva, Nicola Manzella, Simona Gaetani, Tiziana Bacchetti, Massimo Bracci, Veronica Ciarapica, Federica Monaco, Battista Borghi, Monica Amati, Gianna Ferretti, Marco Tomasetti
Pesticides, including herbicides, insecticides and fungicides, are widely used in intensive agriculture. Recently, the long-term effects of pesticide exposure were found to be associated with many diseases. In this study, we evaluated the long-term effect of low-level exposure to a mixture of pesticides on DNA damage response (DDR) in relation to individual detoxifying variability. A residential population chronically exposed to pesticides was enrolled, biological/environmental pesticide levels; paroxonase 1 (PON-1) activity and 192 Q/R polymorphism and DDR were evaluated at three different periods of pesticide exposure...
January 23, 2018: Environmental Toxicology
Dayana R D'Amora, Queenie Hu, Monica Pizzardi, Terrance J Kubiseski
As part of the DNA damage response (DDR) network, the tumour suppressor Breast cancer susceptibility gene 1 (BRCA1) is activated to facilitate DNA repair, transcription and cell cycle control. BRC-1, the Caenorhabditis elegans ortholog of BRCA1, has conserved function in DNA double strand break repair, wherein a loss of brc-1 results in high levels of germline apoptosis. BRAP2/IMP was initially identified as a BRCA1 associated binding protein and previously we have shown that the C. elegans brap-2 deletion mutant experiences BRC-1 dependent larval arrest when exposed to low concentrations of paraquat...
January 22, 2018: Cell Death and Differentiation
Xuanmao Jiao, Marco A Velasco-Velázquez, Min Wang, Zhiping Li, Hallgeir Rui, Amy R Peck, James E Korkola, Xuelian Chen, Shaohua Xu, James B DuHadaway, Sandra Guerrero-Rodriguez, Sankar Addya, Daniela Sicoli, Zhaomei Mu, Gang Zhang, Andres Stucky, Xi Zhang, Massimo Cristofanilli, Alessandro Fatatis, Joe W Gray, Jiang F Zhong, George C Prendergast, Richard G Pestell
The functional significance of the chemokine receptor CCR5 in human breast cancer (BCa) epithelial cells is poorly understood. Here we report that CCR5 expression in human breast cancer correlates with poor outcome. CCR5+ BCa epithelial cells formed mammospheres and initiated tumors with >60-fold greater efficiency in mice. Reintroduction of CCR5 expression into CCR5-negative BCa cells promoted tumor metastases and induced DNA repair gene expression and activity. CCR5 antagonists Maraviroc and Vicriviroc dramatically enhanced cell killing mediated by DNA-damaging chemotherapeutic agents...
January 22, 2018: Cancer Research
Karl H Pang, Francesco Esperto, Aidan P Noon
Bladder cancer (BC) is a common disease in both sexes and majority of cases present as non-muscle invasive BC (NMIBC). The percentage of NMIBC progressing to muscle invasive BC (MIBC) varies between 25% and 75% and currently there are no reliable biomarkers that may predict the outcome of high-risk (HR) NMIBC. Whilst The Cancer Genome Atlas (TCGA) project has identified genetic alteration in MIBC using next-generation sequencing (NGS), genetic data in HR-NMIBC outcome prediction using this new technology are limited...
December 2017: Translational Andrology and Urology
Anna Strzeszewska, Olga Alster, Grażyna Mosieniak, Agata Ciolko, Ewa Sikora
Senescence of cancer cells is an important outcome of treatment of many cancer types. Cell senescence is a permanent cell cycle arrest induced by stress conditions, including DNA damage. DNA damage activates DNA damage response (DDR), which involves members of the phosphatidylinositol 3-kinase-related kinase (PIKK) superfamily: protein kinases ATM, ATR, and DNA-PKcs. The so-far collected data indicate that ATM, with its downstream targets CHK2, p53, and p21, is the key protein involved in DDR-dependent senescence...
January 19, 2018: Cell Death & Disease
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