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    Evidence for the Deregulation of Protein Turnover Pathways in Atm-Deficient Mouse Cerebellum: An Organotypic Study.
    J Neuropathol Exp Neurol 2017 May 23. Epub 2017 May 23.
    From the Department of Biochemistry & Molecular Biology, LSU Health Sciences Center-School of Medicine, New Orleans, Louisiana (CDK, RER, MAJ, SDD); and Biostatistics Program, LSU Health Sciences Center-School of Public Health, New Orleans, Louisiana (ZF).
    Interferon-stimulated gene 15 (ISG15), an antagonist of the ubiquitin pathway, is elevated in cells and brain tissues obtained from ataxia telangiectasia (A-T) patients. Previous studies reveal that an elevated ISG15 pathway inhibits ubiquitin-dependent protein degradation, leading to activation of basal autophagy as a compensatory mechanism for protein turnover in A-T cells. Also, genotoxic stress (ultraviolet [UV] radiation) deregulates autophagy and induces aberrant degradation of ubiquitylated proteins in A-T cells. Read More

    MiR-2964a-5p binding site SNP regulates ATM expression contributing to age-related cataract risk.
    Oncotarget 2017 May 3. Epub 2017 May 3.
    Eye Institute, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China.
    This study was to explore the involvement of DNA repair genes in the pathogenesis of age-related cataract (ARC). We genotyped nine single nucleotide polymorphisms (SNPs) of genes responsible to DNA double strand breaks (DSBs) in 804 ARC cases and 804 controls in a cohort of eye diseases in Chinese population and found that the ataxia telangiectasia mutated (ATM) gene-rs4585:G>T was significantly associated with ARC risk. An in vitro functional test found that miR-2964a-5p specifically down-regulated luciferase reporter expression and ATM expression in the cell lines transfected with rs4585 T allele compared to rs4585 G allele. Read More

    Structures of closed and open conformations of dimeric human ATM.
    Sci Adv 2017 May 10;3(5):e1700933. Epub 2017 May 10.
    Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, UK.
    ATM (ataxia-telangiectasia mutated) is a phosphatidylinositol 3-kinase-related protein kinase (PIKK) best known for its role in DNA damage response. ATM also functions in oxidative stress response, insulin signaling, and neurogenesis. Our electron cryomicroscopy (cryo-EM) suggests that human ATM is in a dynamic equilibrium between closed and open dimers. Read More

    The Herpesvirus Nuclear Egress Complex Component, UL31, Can Be Recruited to Sites of DNA Damage Through Poly-ADP Ribose Binding.
    Sci Rep 2017 May 15;7(1):1882. Epub 2017 May 15.
    Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Canada.
    The herpes simplex virus (HSV) UL31 gene encodes a conserved member of the herpesvirus nuclear egress complex that not only functions in the egress of DNA containing capsids from the nucleus, but is also required for optimal replication of viral DNA and its packaging into capsids. Here we report that the UL31 protein from HSV-2 can be recruited to sites of DNA damage by sequences found in its N-terminus. The N-terminus of UL31 contains sequences resembling a poly (ADP-ribose) (PAR) binding motif suggesting that PAR interactions might mediate UL31 recruitment to damaged DNA. Read More

    Quantitative Mass Spectrometry by Isotope Dilution and Multiple Reaction Monitoring (MRM).
    Methods Mol Biol 2017 ;1606:313-332
    Inova Dwight and Martha Schar Cancer Institute, 3300 Gallows Road, Falls Church, VA, 22042, USA.
    Selected reaction monitoring (SRM) is used in molecular profiling to detect and quantify specific known proteins in complex mixtures. Using isotope dilution (Barnidge et al., Anal Chem 75(3):445-451, 2003) methodologies, peptides can be quantified without the need for an antibody-based method. Read More

    USP7 inhibition alters homologous recombination repair and targets CLL cells independent of ATM/p53 functional status.
    Blood 2017 May 11. Epub 2017 May 11.
    Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, United Kingdom;
    The role of the deubiquitylase ubiquitin-specific protease 7 (USP7) in the regulation of the p53-dependent DNA damage response (DDR) pathway is well established. Whilst previous studies have mostly focused on the mechanisms underlying how USP7 directly controls p53 stability, we have recently shown that USP7 modulates the stability of the DNA damage responsive E3 ubiquitin ligase, RAD18. This suggests that targeting USP7 may have therapeutic potential even in tumors with defective p53 or ibrutinib resistance. Read More

    A coordinated DNA damage response promotes adult quiescent neural stem cell activation.
    PLoS Biol 2017 May 10;15(5):e2001264. Epub 2017 May 10.
    Genome Damage and Stability Centre, Life Sciences, University of Sussex, Brighton, United Kingdom.
    Stem and differentiated cells frequently differ in their response to DNA damage, which can determine tissue sensitivity. By exploiting insight into the spatial arrangement of subdomains within the adult neural subventricular zone (SVZ) in vivo, we show distinct responses to ionising radiation (IR) between neural stem and progenitor cells. Further, we reveal different DNA damage responses between neonatal and adult neural stem cells (NSCs). Read More

    A new ataxia-telangiectasia mutation in an 11-year-old female.
    Immunogenetics 2017 May 9. Epub 2017 May 9.
    Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases, NRITLD, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
    Ataxia-telangiectasia (A-T), a rare inherited disorder, usually affects the nervous and immune systems, and occasionally other organs. A-T is associated mainly with mutations in the ataxia telangiectasia mutated (ATM) gene, which encodes a protein kinase that has a major role in the cellular response to DNA damage. We report here a novel ATM mutation (c. Read More

    Role of ataxia-telangiectasia mutated in hydrogen peroxide preconditioning against oxidative stress in Neuro-2a cells.
    Mol Med Rep 2017 Jun 25;15(6):4280-4285. Epub 2017 Apr 25.
    Department of Pharmacy, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China.
    Ischemic preconditioning is an endogenous protective mechanism that may be triggered by exposure to hydrogen peroxide (H2O2). However, the exact mechanisms underlying preconditioning remain to be fully understood. Ataxia-telangiectasia mutated (ATM) is regarded as an essential endogenous protective protein against stress. Read More

    The DNA damage response (DDR) is induced by the C9orf72 repeat expansion in Amyotrophic Lateral Sclerosis.
    Hum Mol Genet 2017 May 8. Epub 2017 May 8.
    Department of Biomedical Sciences, Faculty of Medicine & Health Sciences, 2 Technology Place | Macquarie University | NSW | 2109, T?+?61 2 9850 2772?+?61 2 9850 2772 | F?+?61 2 9850 2701 | Email:
    Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease affecting motor neurons. Hexanucleotide (GGGGCC) repeat expansions in a non-coding region of C9orf72 are the major cause of familial ALS and frontotemporal dementia (FTD) worldwide. The C9orf72 repeat expansion undergoes repeat-associated non-ATG (RAN) translation to produce five dipeptide repeat proteins (DRPs), including poly(GR) and poly(PR). Read More

    Monitoring the ATM-Mediated DNA Damage Response in the Cerebellum Using Organotypic Cultures.
    Methods Mol Biol 2017 ;1599:419-430
    The David and Inez Myers Laboratory for Cancer Research, Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel.
    The ATM gene and its protein product, the ATM protein kinase, were identified as a result of attempts to understand the molecular basis of the genetic disorder, ataxia-telangiectasia (A-T). The cardinal symptom of A-T is neurodegeneration expressed primarily as progressive cerebellar atrophy. A major tool in the investigation of ATM functions in the cerebellum is cerebellar organotypic cultures, which allow cerebellar slices to live in culture for several weeks without losing their viability and organization. Read More

    Lentiviral Reprogramming of A-T Patient Fibroblasts to Induced Pluripotent Stem Cells.
    Methods Mol Biol 2017 ;1599:401-418
    Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, St. Lucia, Brisbane, QLD, 4072, Australia.
    Reprogramming of cells enables generation of pluripotent stem cells and resulting progeny through directed differentiation, making this technology an invaluable tool for the study of human development and disease. Reprogramming occurs with a wide range of efficiency, a culmination of intrinsic and extrinsic factors including the tissue of origin, the passage number and culture history of the target cells. Another major factor affecting reprogramming is the methodology used and the quality of the reprogramming process itself, including for conventional viral-based approaches viral titer and subsequent viral transduction efficiency, including downstream transgene insertion and stoichiometry. Read More

    A Patient-Specific Stem Cell Model to Investigate the Neurological Phenotype Observed in Ataxia-Telangiectasia.
    Methods Mol Biol 2017 ;1599:391-400
    Eskitis Institute for Drug Discovery, Griffith University, Nathan, QLD, 4111, Australia.
    The molecular pathogenesis of ataxia-telangiectasia (A-T) is not yet fully understood, and a versatile cellular model is required for in vitro studies. The occurrence of continuous neurogenesis and easy access make the multipotent adult stem cells from the olfactory mucosa within the nasal cavity a potential cellular model. We describe an efficient method to establish neuron-like cells from olfactory mucosa biopsies derived from A-T patients for the purpose of studying the cellular and molecular aspects of this debilitating disease. Read More

    DNA Damage Response in Human Stem Cells and Neural Descendants.
    Methods Mol Biol 2017 ;1599:375-390
    Department of Radiation Oncology and the Massey Cancer Center, Virginia Commonwealth University, 401 College Street, Richmond, VA, 23298-0058, USA.
    Glial cells are crucial for the normal function of neurons and are intricately involved in the pathogenesis of neurodegenerative diseases as well as neurologic malignancies. A deeper understanding of the mechanisms by which glial cells influence the development of such pathologies will undoubtedly lead to new and improved therapeutic approaches. Commercially available human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs), both of which can be differentiated into neural progenitors (NPs) and various neural cell lineages, have become widely used as sources for producing normal human central nervous system (CNS) cells. Read More

    Study of ATM Phosphorylation by Cdk5 in Neuronal Cells.
    Methods Mol Biol 2017 ;1599:363-374
    Department of Pharmacology, Emory University School of Medicine, 505-L Whitehead Biomedical Research Building, 615 Michael Street, Atlanta, GA, 30322-3090, USA.
    The phosphatidylinositol-3-kinase-like kinase ATM (ataxia-telangiectasia mutated) plays a central role in coordinating the DNA damage responses including cell cycle checkpoint control, DNA repair, and apoptosis. Mutations of ATM cause a spectrum of defects ranging from neurodegeneration to cancer predisposition. We previously showed that Cdk5 (cyclin-dependent kinase 5) is activated by DNA damage and directly phosphorylates ATM at serine 794 in postmitotic neurons. Read More

    Noncanonical ATM Activation and Signaling in Response to Transcription-Blocking DNA Damage.
    Methods Mol Biol 2017 ;1599:347-361
    Department of Molecular Genetics, Cancer Genomics Netherlands, Erasmus University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands.
    Environmental genotoxins and metabolic byproducts generate DNA lesions that can cause genomic instability and disrupt tissue homeostasis. To ensure genomic integrity, cells employ mechanisms that convert signals generated by stochastic DNA damage into organized responses, including activation of repair systems, cell cycle checkpoints, and apoptotic mechanisms. DNA damage response (DDR) signaling pathways coordinate these responses and determine cellular fates in part, by transducing signals that modulate RNA metabolism. Read More

    Phenotypic Analysis of ATM Protein Kinase in DNA Double-Strand Break Formation and Repair.
    Methods Mol Biol 2017 ;1599:317-334
    Department of Obstetrics and Gynaecology, The University of Ulm, Prittwitzstrasse 43, 89075, Ulm, Germany.
    Ataxia telangiectasia mutated (ATM) encodes a serine/threonine protein kinase, which is involved in various regulatory processes in mammalian cells. Its best-known role is apical activation of the DNA damage response following generation of DNA double-strand breaks (DSBs). When DSBs appear, sensor and mediator proteins are recruited, activating transducers such as ATM, which in turn relay a widespread signal to a multitude of downstream effectors. Read More

    Statistical Analysis of ATM-Dependent Signaling in Quantitative Mass Spectrometry Phosphoproteomics.
    Methods Mol Biol 2017 ;1599:229-244
    Children's Medical Research Institute, University of Sydney, 214 Hawkesbury Road, Westmead, NSW, 2145, Australia.
    Ataxia-telangiectasia mutated (ATM) is a serine/threonine protein kinase, which when perturbed is associated with modified protein signaling that ultimately leads to a range of neurological and DNA repair defects. Recent advances in phospho-proteomics coupled with high-resolution mass-spectrometry provide new opportunities to dissect signaling pathways that ATM utilize under a number of conditions. This chapter begins by providing a brief overview of ATM function, its various regulatory roles and then leads into a workflow focused on the use of the statistical programming language R, together with code, for the identification of ATM-dependent substrates in the cytoplasm. Read More

    ATM Activation and H2AX Phosphorylation Induced by Genotoxic Agents Assessed by Flow- and Laser Scanning Cytometry.
    Methods Mol Biol 2017 ;1599:183-196
    Department of Pathology, Brander Cancer Research Institute, New York Medical College, Basic Sciences Building, 15 Dana Road, Valhalla, NY, 10595, USA.
    Activation of Ataxia Telangiectasia Mediated protein kinase (ATM) by its phosphorylation on serine 1981 and phosphorylation of histone H2AX on serine 139 (γH2AX) are the key events reporting DNA damage, primarily formation of DNA double strand breaks. These events are detected immunocytochemically in individual cells using phospho-specific Abs. The protocols are presented that describe the methodology of immunofluorescent labeling of cells in conjunction with specific staining of cellular DNA. Read More

    Studies of ATM Kinase Activity Using Engineered ATM Sensitive to ATP Analogues (ATM-AS).
    Methods Mol Biol 2017 ;1599:145-156
    Division of Refractory and Advanced Cancer, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
    Ataxia-telangiectasia mutated (ATM) protein is a member of the phosphatidylinositol 3-phosphate kinase (PI3-K)-related protein kinase (PIKK) family and is implicated in the initiation of signaling pathways following DNA double strand breaks (DSBs) elicited by exposure to ionizing irradiation (IR) or radiomimetic compounds. Loss of function of the ATM gene product results in the human genetic disorder ataxia-telangiectasia (A-T) characterized by neurodegeneration, immunodeficiency, genomic instability, and cancer predisposition. In response to DSBs, ATM is activated and phosphorylates Ser/Thr-Gln (S/T-Q) sequences on numerous proteins participating in DNA-damage responses. Read More

    Identification of ATM Protein Kinase Phosphorylation Sites by Mass Spectrometry.
    Methods Mol Biol 2017 ;1599:127-144
    University of Queensland Centre for Clinical Research (UQCCR), University of Queensland, Building 71/918, Royal Brisbane & Women's Hospital Campus, Herston, Brisbane, QLD4029, Australia.
    ATM (ataxia-telangiectasia mutated) protein kinase is a key regulator of cellular responses to DNA damage and oxidative stress. DNA damage triggers complex cascade of signaling events leading to numerous posttranslational modification on multitude of proteins. Understanding the regulation of ATM kinase is therefore critical not only for understanding the human genetic disorder ataxia-telangiectasia and potential treatment strategies, but essential for deciphering physiological responses of cells to stress. Read More

    Zn(II)-Phos-Tag SDS-PAGE for Separation and Detection of a DNA Damage-Related Signaling Large Phosphoprotein.
    Methods Mol Biol 2017 ;1599:113-126
    Department of Functional Molecular Science, Institute of Biomedical & Health Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima, 734-8553, Japan.
    In this chapter, we provide a standard protocol for phosphate-affinity sodium dodecyl sulfate-polyacrylamide gel electrophoresis (Zn(2+)-Phos-tag SDS-PAGE). This technique uses a dizinc(II) complex of the phosphate-binding molecule Phos-tag in conjunction with a neutral-pH gel system, Tris [tris(hydroxymethyl)aminomethane], and acetic acid (Tris-AcOH), to detect shifts in the mobility of phosphorylated ataxia telangiectasia-mutated (ATM) kinase. This protocol, which employs a 3% (w/v) polyacrylamide gel strengthened with 0. Read More

    Quantitative and Dynamic Imaging of ATM Kinase Activity by Bioluminescence Imaging.
    Methods Mol Biol 2017 ;1599:97-111
    Center for Molecular Imaging, University of Michigan, Ann Arbor, MI, 48109, USA.
    Ataxia telangiectasia mutated (ATM) is a serine/threonine kinase critical to the cellular DNA damage response, including DNA double strand breaks (DSBs). ATM activation results in the initiation of a complex cascade of events facilitating DNA damage repair, cell cycle checkpoint control, and survival. Traditionally, protein kinases have been analyzed in vitro using biochemical methods (kinase assays using purified proteins or immunological assays) requiring a large number of cells and cell lysis. Read More

    Analyzing ATM Function by Electroporation of Endonucleases and Immunofluorescence Microscopy.
    Methods Mol Biol 2017 ;1599:85-96
    Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan.
    Ataxia-telangiectasia mutated (ATM) protein, which plays a crucial role in DNA damage checkpoint signaling, is activated by DNA double strand breaks (DSBs) caused by ionizing radiation. While radiation exposure induces various types of DNA break ends, here, we describe a method, which enables creating defined types of DSBs by applying restriction endonucleases and foci analysis by immunofluorescence microscopy. The protocol greatly improves our knowledge on specific roles of ATM function in different DNA repair pathways. Read More

    Image-Based High Content Screening: Automating the Quantification Process for DNA Damage-Induced Foci.
    Methods Mol Biol 2017 ;1599:71-84
    QIMR Berghofer Medical Research Institute, 300 Herston Road, Brisbane, QLD, 4006, Australia.
    Visual inspection of cellular activities based on conventional fluorescence microscope is a fundamental tool to study the role of DNA damage response (DDR). In the context of drug discovery where the capture of thousands of images is required across parallel experiments, this presents a challenge to data collection and analysis. Manual scoring is laborious and often reliant on trained personnel to intuit biological meaning through visual reasoning. Read More

    An HTRF(®) Assay for the Protein Kinase ATM.
    Methods Mol Biol 2017 ;1599:43-56
    Eurofins Pharma Discovery Services UK Limited, Gemini Crescent, Dundee Technology Park, Dundee, DD2 1SW, UK.
    Ataxia telangiectasia mutated (ATM) is a serine/threonine kinase that plays a key role in the regulation of DNA damage pathways and checkpoint arrest. In recent years, there has been growing interest in ATM as a therapeutic target due to its association with cancer cell survival following genotoxic stress such as radio- and chemotherapy. Large-scale targeted drug screening campaigns have been hampered, however, by technical issues associated with the production of sufficient quantities of purified ATM and the availability of a suitable high-throughput assay. Read More

    ATM Gene Mutation Detection Techniques and Functional Analysis.
    Methods Mol Biol 2017 ;1599:25-42
    Inserm U830, Institut Curie - Section de Recherche, 26 rue d'Ulm, cedex 5, Paris, 75248, France.
    Ataxia Telangiectasia (A-T) is caused by biallelic inactivation of the Ataxia Telangiectasia Mutated (ATM) gene, due to nonsense or missense mutations, small insertions/deletions (indels), splicing alterations, and large genomic rearrangements. After establishing A-T clinical diagnosis, a molecular confirmation is needed, based on the detection of one of these loss-of-function mutations in at least one allele. In most cases, the pathogenicity of the detected mutations is sufficient to make a definitive diagnosis. Read More

    Assaying for Radioresistant DNA Synthesis, the Hallmark Feature of the Intra-S-Phase Checkpoint Using a DNA Fiber Technique.
    Methods Mol Biol 2017 ;1599:13-23
    University of Queensland Centre for Clinical Research (UQCCR), University of Queensland, Building 71/918, Royal Brisbane & Women's Hospital Campus, Herston, Brisbane, QLD4029, Australia.
    During S-phase the cell replicates its DNA which is critical to maintaining the integrity of the genome and cell survival amidst damaging events. The cell is equipped with a series of checkpoints to slow progress throughout the cycle and facilitate DNA repair. Ataxia telangiectasia mutated (ATM), defective in the human genetic disorder ataxia-telangiectasia (A-T), is the key to initiating a signaling cascade activating the intra-S-phase checkpoint. Read More

    Assaying Radiosensitivity of Ataxia-Telangiectasia.
    Methods Mol Biol 2017 ;1599:1-11
    Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA.
    Ataxia-Telangiectasia (A-T) is a prototypical genomic instability disorder with multi-organ deficiency and it is caused by the defective function of a single gene, ATM (Ataxia-Telangiectasia Mutated). Radiosensitivity, among the pleiotropic symptoms of A-T, reflects the basic physiological functions of ATM protein in the double strand break (DSB)-induced DNA damage response (DDR) and also restrains A-T patients from the conventional radiation therapy for their lymphoid malignancy. In this chapter, we describe two methods that have been developed in our lab to assess the radiosensitivity of A-T patients: (1) Colony Survival Assay (CSA) and (2) Flow Cytometry of phospho-SMC1 (FC-pSMC1). Read More

    Benzo[a]pyrene-induced DNA damage associated with mutagenesis in primary human activated T lymphocytes.
    Biochem Pharmacol 2017 Apr 29. Epub 2017 Apr 29.
    Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche en Santé, Environnement et Travail (IRSET - INSERM UMR 1085), 35000 Rennes, France; Université de Rennes 1, Faculté des Sciences Pharmaceutiques et Biologiques, structure fédérative de recherche, Biosit UMS CNRS 3480/US INSERM 018, 35043 Rennes, France. Electronic address:
    Polycyclic aromatic hydrocarbons (PAHs), such as benzo[a]pyrene (B[a]P), are widely distributed environmental contaminants exerting toxic effects such as genotoxicity and carcinogenicity, mainly associated with aryl hydrocarbon receptor (AhR) activation and the subsequent induction of cytochromes P-450 (CYP) 1-metabolizing enzymes. We previously reported an up-regulation of AhR expression and activity in primary cultures of human T lymphocyte by a physiological activation. Despite the suggested link between exposure to PAHs and the risk of lymphoma, the potential of activated human T lymphocytes to metabolize AhR exogenous ligands such as B[a]P and produce DNA damage has not been investigated. Read More

    Metabolic perturbation of epigenome by inhibiting S-adenosylhomocysteine hydrolase elicits senescence through DNA damage response in hepatoma cells.
    Tumour Biol 2017 May;39(5):1010428317699117
    4 Key Laboratory of Artificial Cells, The Third Central Hospital of Tianjin, Tianjin Medical University, Tianjin, China.
    Cellular senescence is a key physiological barrier against tumor and represents an option for therapeutic intervention. One pivotal intracellular stimulus causing senescence is DNA damage response, while the senescence-associated heterochromatin in cancer limits the strength of the DNA damage response to endogenous genotoxic stress or DNA-damaging agents. Therefore, targeting the maintenance of compacted chromatin in cancer cells represents an optional intervention to improve the therapeutic efficacy in cancer treatment. Read More

    Synergistic effects of a novel lipid-soluble extract from Pinellia pedatisecta Schott and cisplatin on human cervical carcinoma cell lines through the regulation of DNA damage response signaling pathway.
    Oncol Lett 2017 Apr 14;13(4):2121-2128. Epub 2017 Feb 14.
    Department of Integration of Western and Traditional Medicine, Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, P.R. China.
    Herbal medicines have been recognized as an attractive approach for cancer therapy with minimal side effects. The present study investigated the type of interaction between a novel lipid-soluble extract from Pinellia pedatisecta Schott (PE) and cisplatin (CDDP) on human cervical cancer SiHa and CaSki cell lines in vitro. The mechanism of this combination was studied using cell proliferation, invasion and apoptosis assays, and by analyzing cell cycle distribution and protein expression, with a focus on DNA damage response (DDR) activation. Read More

    Susceptibility of ATM-deficient pancreatic cancer cells to radiation.
    Cell Cycle 2017 Apr 28:1-8. Epub 2017 Apr 28.
    a Department of Pathology , The Johns Hopkins University School of Medicine , Baltimore , MD, USA.
    Ataxia telangiectasia mutated (ATM) is inactivated in a significant minority of pancreatic ductal adenocarcinomas and may be predictor of treatment response. We determined if ATM deficiency renders pancreatic cancer cells more sensitive to fractionated radiation or commonly used chemotherapeutics. ATM expression was knocked down in three pancreatic cancer cell lines using ATM-targeting shRNA. Read More

    Targeting the ATR-CHK1 Axis in Cancer Therapy.
    Cancers (Basel) 2017 Apr 27;9(5). Epub 2017 Apr 27.
    Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
    Targeting the DNA damage response (DDR) is a new therapeutic approach in cancer that shows great promise for tumour selectivity. Key components of the DDR are the ataxia telangiectasia mutated and Rad3 related (ATR) and checkpoint kinase 1 (CHK1) kinases. This review article describes the role of ATR and its major downstream target, CHK1, in the DDR and why cancer cells are particularly reliant on the ATR-CHK1 pathway, providing the rationale for targeting these kinases, and validation of this hypothesis by genetic manipulation. Read More

    p53 dynamics in response to DNA damage vary across cell lines and are shaped by efficiency of DNA repair and activity of the kinase ATM.
    Sci Signal 2017 Apr 25;10(476). Epub 2017 Apr 25.
    Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
    Cellular systems show a wide range of signaling dynamics. Many of these dynamics are highly stereotyped, such as oscillations at a fixed frequency. However, most studies looking at the role of signaling dynamics focus on one or a few cell lines, leaving the diversity of dynamics across tissues or cell lines a largely unexplored question. Read More

    Inhibition of ATR potentiates the cytotoxic effect of gemcitabine on pancreatic cancer cells through enhancement of DNA damage and abrogation of ribonucleotide reductase induction by gemcitabine.
    Oncol Rep 2017 Apr 19. Epub 2017 Apr 19.
    National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering, The Ministry of Education, School of Life Sciences, Jilin University, Changchun, Jilin 130012, P.R. China.
    Pancreatic cancer is a highly malignant disease with a dismal prognosis. Gemcitabine (GEM)-based chemotherapy is the first-line treatment for patients with advanced disease, although its efficacy is very limited, mainly due to drug resistance. Ataxia telangiectasia and Rad3-related (ATR) plays a critical role in the DNA damage response (DDR) which has been implicated in GEM resistance. Read More

    Effects of low dose ionizing radiation on DNA damage-caused pathways by reverse-phase protein array and Bayesian networks.
    J Bioinform Comput Biol 2017 Apr;15(2):1750006
    ‡ Department of Computer Science and Engineering, University of Texas at Arlington, Arlington, TX76019, USA.
    Ionizing radiation (IR) causing damages to Deoxyribonucleic acid (DNA) constitutes a broad range of base damage and double strand break, and thereby, it induces the operation of relevant signaling pathways such as DNA repair, cell cycle control, and cell apoptosis. The goal of this paper is to study how the exposure to low dose radiation affects the human body by observing the signaling pathway associated with Ataxia Telangiectasia mutated (ATM) using Reverse-Phase Protein Array (RPPA) and isogenic human Ataxia Telangiectasia (A-T) cells under different amounts and durations of IR exposure. In order to verify which proteins could be involved in a DNA damage-caused pathway, only proteins that highly interact with each other under IR are selected by using correlation coefficient. Read More

    MRE11 stability is regulated by CK2-dependent interaction with R2TP complex.
    Oncogene 2017 Apr 24. Epub 2017 Apr 24.
    Department of Cancer Cell Biology, Institute of Molecular Genetics of the ASCR, Prague, Czech Republic.
    The MRN (MRE11-RAD50-NBS1) complex is essential for repair of DNA double-strand breaks and stalled replication forks. Mutations of the MRN complex subunit MRE11 cause the hereditary cancer-susceptibility disease ataxia-telangiectasia-like disorder (ATLD). Here we show that MRE11 directly interacts with PIH1D1, a subunit of heat-shock protein 90 cochaperone R2TP complex, which is required for the assembly of large protein complexes, such as RNA polymerase II, small nucleolar ribonucleoproteins and mammalian target of rapamycin complex 1. Read More

    The DNA Damage Response in Neurons: Die by Apoptosis or Survive in a Senescence-Like State?
    J Alzheimers Dis 2017 Apr 18. Epub 2017 Apr 18.
    Neurons are exposed to high levels of DNA damage from both physiological and pathological sources. Neurons are post-mitotic and their loss cannot be easily recovered from; to cope with DNA damage a complex pathway called the DNA damage response (DDR) has evolved. This recognizes the damage, and through kinases such as ataxia-telangiectasia mutated (ATM) recruits and activates downstream factors that mediate either apoptosis or survival. Read More

    ATM kinase sustains breast cancer stem-like cells by promoting ATG4C expression and autophagy.
    Oncotarget 2017 Mar;8(13):21692-21709
    Instituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Santa Lucia, Rome, Italy.
    The efficacy of Ataxia-Telangiectasia Mutated (ATM) kinase signalling inhibition in cancer therapy is tempered by the identification of new emerging functions of ATM, which suggests that the role of this protein in cancer progression is complex. We recently demonstrated that this tumor suppressor gene could act as tumor promoting factor in HER2 (Human Epidermal Growth Factor Receptor 2) positive breast cancer. Herein we put in evidence that ATM expression sustains the proportion of cells with a stem-like phenotype, measured as the capability to form mammospheres, independently of HER2 expression levels. Read More

    Loss of tumour-specific ATM protein expression is an independent prognostic factor in early resected NSCLC.
    Oncotarget 2017 Mar 15. Epub 2017 Mar 15.
    Department of Oncology, Tom Baker Cancer Centre and University of Calgary, Calgary, Alberta T2N 4N2, Canada.
    Ataxia-telangiectasia mutated (ATM) is critical in maintaining genomic integrity. In response to DNA double-strand breaks, ATM phosphorylates downstream proteins involved in cell-cycle checkpoint arrest, DNA repair, and apoptosis. Here we investigate the frequency, and influence of ATM deficiency on outcome, in early-resected non-small cell lung cancer (NSCLC). Read More

    Outcome of hematopoietic cell transplantation for DNA double-strand break repair disorders.
    J Allergy Clin Immunol 2017 Apr 7. Epub 2017 Apr 7.
    Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom; Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom. Electronic address:
    Background: Rare DNA breakage repair disorders predispose to infection and lymphoreticular malignancies. Hematopoietic cell transplantation (HCT) is curative, but coadministered chemotherapy or radiotherapy is damaging because of systemic radiosensitivity. We collected HCT outcome data for Nijmegen breakage syndrome, DNA ligase IV deficiency, Cernunnos-XRCC4-like factor (Cernunnos-XLF) deficiency, and ataxia-telangiectasia (AT). Read More

    Compartmentalization of DNA Damage Response between Heterochromatin and Euchromatin Is Mediated by Distinct H2A Histone Variants.
    Curr Biol 2017 Apr 6;27(8):1192-1199. Epub 2017 Apr 6.
    Gregor Mendel Institute (GMI), Austrian Academy of Sciences, Vienna Biocenter (VBC), Dr. Bohr-Gasse 3, 1030 Vienna, Austria. Electronic address:
    DNA double-strand break (DSB) repair depends on the ataxia telangiectasia mutated (ATM) kinase that phosphorylates the conserved C-terminal SQ motif present in the histone variant H2A.X [1-7]. In constitutive heterochromatin of mammals, DSB repair is delayed and relies on phosphorylation of the proteins HP1 and KAP1 by ATM [2, 8-14]. Read More

    CHK1-targeted therapy to deplete DNA replication-stressed, p53-deficient, hyperdiploid colorectal cancer stem cells.
    Gut 2017 Apr 7. Epub 2017 Apr 7.
    Institute of General Pathology, Catholic University and A. Gemelli Polyclinic, Rome, Italy.
    Objective: Cancer stem cells (CSCs) are responsible for tumour formation and spreading, and their targeting is required for tumour eradication. There are limited therapeutic options for advanced colorectal cancer (CRC), particularly for tumours carrying RAS-activating mutations. The aim of this study was to identify novel CSC-targeting strategies. Read More

    Beta-Ecdysone Protects Mouse Osteoblasts from Glucocorticoid-Induced Apoptosis In Vitro.
    Planta Med 2017 Apr 7. Epub 2017 Apr 7.
    Center for Musculoskeletal Health, Internal Medicine, University of California at Davis Medical Center, Sacramento, CA, USA.
    Glucocorticoid-induced osteoporosis is a common form of secondary osteoporosis. Glucocorticoids affect both bone formation and resorption, and prolonged glucocorticoid exposure can suppress osteoblast activities. beta-Ecdysone, found in many plants, is involved in protein synthesis, carbohydrate and lipid metabolism, and immunologic modulation. Read More

    Microvesicles Contribute to the Bystander Effect of DNA Damage.
    Int J Mol Sci 2017 Apr 7;18(4). Epub 2017 Apr 7.
    Division of Nephrology, Department of Medicine, McMaster University, Hamilton, ON L8N 4A6, Canada.
    Genotoxic treatments elicit DNA damage response (DDR) not only in cells that are directly exposed but also in cells that are not in the field of treatment (bystander cells), a phenomenon that is commonly referred to as the bystander effect (BE). However, mechanisms underlying the BE remain elusive. We report here that etoposide and ultraviolet (UV) exposure stimulate the production of microvesicles (MVs) in DU145 prostate cancer cells. Read More

    NBS1 is regulated by two kind of mechanisms: ATM-dependent complex formation with MRE11 and RAD50, and cell cycle-dependent degradation of protein.
    J Radiat Res 2017 Mar 22:1-8. Epub 2017 Mar 22.
    Laboratory of Stress Response Biology, Graduate School of Science, Kyoto University, Kitashirakawa-oiwakecho, Sakyo-ku, Kyoto 606-8501, Japan.
    Nijmegen breakage syndrome (NBS), a condition similar to Ataxia-Telangiectasia (A-T), is a radiation-hypersensitive genetic disorder showing chromosomal instability, radio-resistant DNA synthesis, immunodeficiency, and predisposition to malignances. The product of the responsible gene, NBS1, forms a complex with MRE11 and RAD50 (MRN complex). The MRN complex is necessary for the DNA damage-induced activation of ATM. Read More

    In vitro prediction of breast cancer therapy toxicity.
    Ann Transl Med 2017 Mar;5(5):94
    North Coast Cancer Institute, Lismore, 2480 NSW, Australia.
    Background: Understanding the basis of clinical radiosensitivity is a key goal of radiation research. In this study, we used the limiting dilution assay (LDA) to analyze in vitro radiosensitivity of cell lines from individuals with breast and other cancers, who had been treated with ionizing radiation, and who either had a non-radiosensitive (RS) radiation response or who were clinically RS.

    Methods: Lymphoblastoid cell lines (LCLs) were created from 29 cancer patients including 19 RS patients, 10 controls who had not developed severe normal tissue reactions, and 1 ataxia telangiectasia RS control cell line. Read More

    Brain edema with clasmatodendrosis complicating ataxia telangiectasia.
    Brain Dev 2017 Mar 25. Epub 2017 Mar 25.
    Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Japan; Department of Developmental Medical Sciences, Graduate School of Medicine, The University of Tokyo, Japan.
    Ataxia-telangiectasia is a chronic progressive disorder affecting the nervous and immune systems, caused by a genetic defect in the ATM protein. Clasmatodendrosis, a distinct form of astroglial death, has rarely been reported in ataxia-telangiectasia. Neuropathology of our patient disclosed diffuse edema of the cerebral and cerebellar white matter with prominent clasmatodendrosis, implicating ATM in the regulation of astroglial cell death. Read More

    Novel tetrahydroacridine and cyclopentaquinoline derivatives with fluorobenzoic acid moiety induce cell cycle arrest and apoptosis in lung cancer cells by activation of DNA damage signaling.
    Tumour Biol 2017 Mar;39(3):1010428317695011
    3 Department of Clinical Chemistry and Biochemistry, Medical University of Lodz, Łódź, Poland.
    Lung cancer is still the leading cause of cancer-related death worldwide, indicating a necessity to develop more effective therapy. Acridine derivatives are potential anticancer agents due to their ability to intercalate DNA as well as inhibit enzymes involved in replication and transcription. Recently, we have evaluated anticancer activity of 32 novel acridine-based compounds. Read More

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