Search our Database of Scientific Publications and Authors

I’m looking for a

    8755 results match your criteria Ataxia-Telangiectasia

    1 OF 176

    Ataxia Telangiectasia-Mutated (ATM)Polymorphisms and Risk of Lung Cancer in a Chinese Population.
    Front Public Health 2017 8;5:102. Epub 2017 Jun 8.
    Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, State University of New York (SUNY) at Buffalo, Buffalo, NY, United States.
    Background: The ataxia telangiectasia-mutated (ATM) gene has a key role in DNA repair including activation and stabilization of p53, which implicates the importance of ATM polymorphisms in the development of cancer. This study aims to investigate the association of two ATM single-nucleotide polymorphisms (SNPs) with lung cancer, as well as their potential interaction with p53 gene and other known risk factors of lung cancer.

    Methods: A population-based case-control study was conducted in Taiyuan city, China with 399 cases and 466 controls matched on the distribution of age and sex of cases. Read More

    Inner retinal dystrophy in a patient with biallelic sequence variants in BRAT1.
    Ophthalmic Genet 2017 Mar 2:1-3. Epub 2017 Mar 2.
    a Department of Ophthalmology , University of California , San Francisco, San Francisco , California , USA.
    Background: Mutations in the BRCA1-associated protein required for the ataxia telangiectasia mutated (ATM) activation-1 (BRAT1) gene cause lethal neonatal rigidity and multifocal seizure syndrome characterized by rigidity and intractable seizures and a milder phenotype with intellectual disability, seizures, nonprogressive cerebellar ataxia or dyspraxia, and cerebellar atrophy. To date, nystagmus, cortical visual impairment, impairment of central vision, optic nerve hypoplasia, and optic atrophy have been described in this condition. This article describes the retinal findings in a patient with biallelic deleterious sequence variants in BRAT1. Read More

    ATM, radiation, and the risk of second primary breast cancer.
    Int J Radiat Biol 2017 Jun 19:1-27. Epub 2017 Jun 19.
    b Genetics Institute and Department of Pathology, Immunology and Laboratory Medicine , University of Florida , P.O. Box 103610 , Gainesville , FL 32610-3610.
    Purpose: It was first suggested more than 40 years ago that heterozygous carriers for the human autosomal recessive disorder Ataxia-Telangiectasia (A-T) might also be at increased risk for cancer. Subsequent studies have identified the responsible gene, Ataxia-Telangiectasia Mutated (ATM), characterized genetic variation at this locus in A-T and a variety of different cancers, and described the functions of the ATM protein with respect to cellular DNA damage responses. However, an overall model of how ATM contributes to cancer risk, and in particular, the role of DNA damage in this process, remains lacking. Read More

    Taming Tricky DSBs: ATM on duty.
    DNA Repair (Amst) 2017 Jun 9. Epub 2017 Jun 9.
    LBCMCP, Centre de Biologie Intégrative (CBI), CNRS, Université de Toulouse, UT3, France. Electronic address:
    Ataxia Telangiectasia Mutated (ATM) has been known for decades as the main kinase mediating the DNA Double-Strand Break Response (DDR). Extensive studies have revealed its dual role in locally promoting detection and repair of DSBs as well as in activating global DNA damage checkpoints. However, recent studies pinpoint additional unanticipated functions for ATM in modifying both the local chromatin landscape and the global chromosome organization, more particularly at persistent breaks. Read More

    RUG3 is a negative regulator of plant responses to ABA in Arabidopsis thaliana.
    Plant Signal Behav 2017 Jun 14. Epub 2017 Jun 14.
    a State Key Laboratory of Agricultural Microbiology, College of Plant Science and Technology Huazhong Agricultural University. Wuhan 430070 , P.R. China.
    Mitochondria is a main target of various stressors. Dysfunction of mitochondria stimulates overproduction of reactive oxygen species (ROS), which can cause oxidative damage to mitochondria and DNA. Recently, we demonstrated that RCC1/UVR8/GEF-like 3 (RUG3), a member of the Regulator of Chromatin Condensation 1 (RCC1) protein family, can directly interact with ataxia telangiectasia mutated (ATM), a key regulator of the DNA damage response (DDR), and synergistically regulates the alternative splicing of mitochondrial nad2. Read More

    [The Role of DNA Double-strain Damage Repairing Mechanisms in Diabetic Atheroscolersis].
    Sichuan Da Xue Xue Bao Yi Xue Ban 2017 Mar;48(2):191-196
    Department of Gerontology, Nanchong Central Hospital, Nanchong 637000, China.
    Objectives: To identify the role of DNA double-strain damage repairing pathway in the development of diabetics atherosclerosis.

    Methods: Wistar male rats were randomly divided into three groups: control group (group A), balloon injury group (group B) and diabetes + balloon injury group (group C). Streptozotocin (STZ) was injected into rat abdomen to induce diabetes. Read More

    Familial Pancreatic Cancer and the Future of Directed Screening.
    Gut Liver 2017 Jun 15. Epub 2017 Jun 15.
    Samuel F. Bronfman Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
    Pancreatic cancer (PC) is the third most common cause of cancer-related death in the United States and the 12th most common worldwide. Mortality is high, largely due to late stage of presentation and suboptimal treatment regimens. Approximately 10% of PC cases have a familial basis. Read More

    Epstein-Barr virus-induced up-regulation of TCAB1 is involved in the DNA damage response in nasopharyngeal carcinoma.
    Sci Rep 2017 Jun 12;7(1):3218. Epub 2017 Jun 12.
    State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.
    Telomerase Cajal body protein 1 (TCAB1), which is involved in Cajal body maintenance, telomere elongation and ribonucleoprotein biogenesis, has been linked to cancer predisposition, including nasopharyngeal carcinoma (NPC), due to its oncogenic properties. However, there are no specific reports to date on the functional relevance of TCAB1 and Epstein-Barr virus (EBV), which is considered to be a risk factor for NPC. In this study, we first examined NPC clinical tissues and found a notable overexpression of TCAB1 in EBV-positive specimens. Read More

    p21 maintains senescent cell viability under persistent DNA damage response by restraining JNK and caspase signaling.
    EMBO J 2017 Jun 12. Epub 2017 Jun 12.
    Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel
    Cellular senescence is a permanent state of cell cycle arrest that protects the organism from tumorigenesis and regulates tissue integrity upon damage and during tissue remodeling. However, accumulation of senescent cells in tissues during aging contributes to age-related pathologies. A deeper understanding of the mechanisms regulating the viability of senescent cells is therefore required. Read More

    JS-K, a nitric oxide prodrug, induces DNA damage and apoptosis in HBV-positive hepatocellular carcinoma HepG2.2.15 cell.
    Biomed Pharmacother 2017 Jun 8;92:989-997. Epub 2017 Jun 8.
    Key Laboratory of infectious disease, Provincial Department of Education, Zunyi Medical College Guizhou, 563000 China; Research Center for Medicine and Biology, Zunyi Medical College, Guizhou, 563000 China; Department of Microbiology, Zunyi Medical College, Guizhou, 563000 China. Electronic address:
    Hepatocellular carcinoma (HCC) is the most important cause of cancer-related death, and 85% of HCC is caused by chronic HBV infection, the prognosis of patients and the reduction of HBV DNA levels remain unsatisfactory. JS-K, a nitric oxide-releasing diazeniumdiolates, is effective against various tumors, but little is known on its effects on HBV positive HCC. We found that JS-K reduced the expression of HBsAg and HBeAg in HBV-positive HepG2. Read More

    Limited nucleotide pools restrict Epstein-Barr virus-mediated B-cell immortalization.
    Oncogenesis 2017 Jun 12;6(6):e349. Epub 2017 Jun 12.
    Department of Molecular Genetics and Microbiology, Center for Virology, Duke University School of Medicine, Durham, NC, USA.
    Activation of cellular oncogenes as well as infection with tumor viruses can promote aberrant proliferation and activation of the host DNA damage response. Epstein-Barr virus (EBV) infection of primary human B cells induces a transient period of hyper-proliferation, but many of these infected cells succumb to an ataxia telangiectasia mutated/checkpoint kinase 2 (ATM/Chk2)-mediated senescence-like growth arrest. In this study, we assessed the role of DNA replicative stress and nucleotide pool levels in limiting EBV-infected B-cell outgrowth. Read More

    Zerumbone Regulates DNA Repair Responding to Ionizing Radiation and Enhances Radiosensitivity of Human Prostatic Cancer Cells.
    Integr Cancer Ther 2017 Jun 1:1534735417712008. Epub 2017 Jun 1.
    1 Mackay Memorial Hospital, Taipei, Taiwan.
    Introduction: Radiation therapy using ionizing radiation is widely used for the treatment of prostate cancer. The intrinsic radiation sensitivity of cancer cells could be enhanced by modulating multiple factors including the capacity to repair DNA damage, especially double-strand breaks (DSBs). We aimed to examine the effect of zerumbone on radiation sensitivity and its protective effects against ionizing radiation-induced DSB in human prostate cancer cells. Read More

    Multicolor Flow Cytometry for the Diagnosis of Primary Immunodeficiency Diseases.
    J Clin Immunol 2017 Jun 8. Epub 2017 Jun 8.
    Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
    Purpose: Primary immunodeficiency diseases (PIDDs) are rare inherited diseases that impair the human immune system. We established a multicolor flow cytometric assay to comprehensively evaluate the immune status and immunological characteristics of patients with PIDDs.

    Methods: Fifty-nine normal controls and 75 patients with PIDDs, including X-linked severe combined immunodeficiency (X-SCID), X-linked agammaglobulinemia (XLA), X-linked hyper IgM syndrome (X-HIGM), ataxia telangiectasia (AT), Wiskott-Aldrich syndrome (WAS), hyper IgE syndrome (HIES), and chronic mucocutaneous candidiasis disease (CMCD), were enrolled in this study. Read More

    Ataxia-Telangiectasia patients get a rare chance to meet the experts at a dedicated workshop in IFOM (the FIRC Institute of Molecular Oncology).
    Ecancermedicalscience 2017 8;11:ed66. Epub 2017 May 8.
    Science Editor, ecancermedicalscience, European Institute of Oncology, Milan, Italy.
    Ataxia telangiectasia (A-T) is a genetic syndrome characterized by cerebellar degeneration, telangiectasia, immunodeficiency and cancer predisposition. A-T occurs in between 1 in 40,000 and 1 in 100,000 live births. The first symptoms normally occur in early childhood when the infant begins to walk. Read More

    DNA damage-induced ATR kinase activation in non-replicating cells is regulated by the XPB subunit of transcription factor II-H (TFIIH).
    J Biol Chem 2017 Jun 7. Epub 2017 Jun 7.
    Wright State University, United States
    The role of the DNA damage response protein kinase ataxia telangiectasia and Rad-3-related (ATR) in the cellular response to DNA damage during the replicative phase of the cell cycle has been extensively studied. However, little is known about ATR kinase function in cells that are not actively replicating DNA and which constitute most cells in the human body. Using small-molecule inhibitors of ATR kinase and overexpression of a kinase-inactive form of the enzyme, I show here that ATR promotes cell death in non-replicating/non-cycling cultured human cells exposed to N-acetoxy-2-acetylaminofluorene (NA-AAF), which generates bulky DNA adducts that block RNA polymerase movement. Read More

    [Study on the Effect of Overexpression of miR-18a on Cellular Proliferation and Migration by Targeting ATM in Human Colorectal Cancer Cells].
    Sichuan Da Xue Xue Bao Yi Xue Ban 2016 Jul;47(4):451-457
    Department of Biochemistry and Molecular Biology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu 610041, China.
    Objectives: To study the regulation to colon cancer cellular biological properties through miR-18a targeting ataxia-telangiectasia mutated gene (ATM).

    Methods: A target of miR-18a was predicted by using bioinformatics tools. The miR-18a mimics and inhibitors were designed and synthesized. Read More

    Targeting Ongoing DNA Damage in Multiple Myeloma: Effects of DNA Damage Response Inhibitors on Plasma Cell Survival.
    Front Oncol 2017 19;7:98. Epub 2017 May 19.
    Cancer Research Center-IBMCC (USAL-CSIC), Salamanca, Spain.
    Human myeloma cell lines (HMCLs) and a subset of myeloma patients with poor prognosis exhibit high levels of replication stress (RS), leading to DNA damage. In this study, we confirmed the presence of DNA double-strand breaks (DSBs) in several HMCLs by measuring γH2AX and RAD51 foci and analyzed the effect of various inhibitors of the DNA damage response on MM cell survival. Inhibition of ataxia telangiectasia and Rad3-related protein (ATR), the main kinase mediating the response to RS, using the specific inhibitor VE-821 induced more cell death in HMCLs than in control lymphoblastoid cells and U266, an HMCL with a low level of DNA damage. Read More

    NOX2-dependent ATM kinase activation dictates pro-inflammatory macrophage phenotype and improves effectiveness to radiation therapy.
    Cell Death Differ 2017 Jun 2. Epub 2017 Jun 2.
    Cell Death and Aging Team, Gustave Roussy, 114 rue Edouard Vaillant, Villejuif F-94805, France.
    Although tumor-associated macrophages have been extensively studied in the control of response to radiotherapy, the molecular mechanisms involved in the ionizing radiation-mediated activation of macrophages remain elusive. Here we show that ionizing radiation induces the expression of interferon regulatory factor 5 (IRF5) promoting thus macrophage activation toward a pro-inflammatory phenotype. We reveal that the activation of the ataxia telangiectasia mutated (ATM) kinase is required for ionizing radiation-elicited macrophage activation, but also for macrophage reprogramming after treatments with γ-interferon, lipopolysaccharide or chemotherapeutic agent (such as cisplatin), underscoring the fact that the kinase ATM plays a central role during macrophage phenotypic switching toward a pro-inflammatory phenotype through the regulation of mRNA level and post-translational modifications of IRF5. Read More

    Recommendations for Childhood Cancer Screening and Surveillance in DNA Repair Disorders.
    Clin Cancer Res 2017 Jun;23(11):e23-e31
    National Cancer Institute, Rockville, Maryland.
    DNA repair syndromes are heterogeneous disorders caused by pathogenic variants in genes encoding proteins key in DNA replication and/or the cellular response to DNA damage. The majority of these syndromes are inherited in an autosomal-recessive manner, but autosomal-dominant and X-linked recessive disorders also exist. The clinical features of patients with DNA repair syndromes are highly varied and dependent on the underlying genetic cause. Read More

    Pravastatin reduces radiation-induced damage in normal tissues.
    Exp Ther Med 2017 May 8;13(5):1765-1772. Epub 2017 Mar 8.
    Department of Radiology, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
    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. Read More

    Silencing of ATM expression by siRNA technique contributes to glioma stem cell radiosensitivity in vitro and in vivo.
    Oncol Rep 2017 Jul 24;38(1):325-335. Epub 2017 May 24.
    Department of Oncology, Chongqing Cancer Institute, Chongqing 400030, P.R. China.
    Evidence has shown that both high expression of the ataxia-telangiectasia mutated (ATM) gene and glioma stem cells (GSCs) are responsible for radioresistance in glioma. Thus, we hypothesized that brain tumor radiosensitivity may be enhanced via silencing of the ATM gene in GSCs. In the present study we successfully induced GSCs from two cell lines and used CD133 and nestin to identify GSCs. Read More

    Intermittent low dose irradiation enhances the effectiveness of radio- and chemo-therapy for human colorectal adenocarcinoma cell line HT-29.
    Oncol Rep 2017 Jul 30;38(1):591-597. Epub 2017 May 30.
    Department of Vascular Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China.
    Low dose irradiation (LDIR) induces hormesis and adaptive response in organism and mammalian cell lines. Notably, LDIR generates distinct biological effects in cancer cells from normal cells, e.g. Read More

    The G2 checkpoint inhibitor CBP-93872 increases the sensitivity of colorectal and pancreatic cancer cells to chemotherapy.
    PLoS One 2017 30;12(5):e0178221. Epub 2017 May 30.
    Department of Cell Biology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Aichi, Japan.
    CBP-93872 suppresses maintenance of DNA double-stranded break-induced G2 checkpoint, by inhibiting the pathway between ataxia-telangiectasia mutated (ATM) and ATM- and Rad3-related (ATR) activation. To examine the potential use of CBP-93872 for clinical applications, we analyzed the synergistic effects of platinum-containing drugs, oxaliplatin and cisplatin, pyrimidine antimetabolites, gemcitabine and 5-fluorouracil (5-FU), in combination with CBP-93872, on cell lethality in colorectal and pancreatic cancer cell lines. Treatment with CBP-93872 significantly increased cancer cell sensitivities to various chemotherapeutic agents tested through suppression of checkpoint activation. Read More

    Recent advances in the study of immunodeficiency and DNA damage response.
    Int J Hematol 2017 May 26. Epub 2017 May 26.
    Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
    DNA breaks can be induced by exogenous stimuli or by endogenous stress, but are also generated during recombination of V, D, and J genes (V(D)J recombination), immunoglobulin class switch recombination (CSR). Among various DNA breaks generated, DNA double strand break (DSB) is the most deleterious one. DNA damage response (DDR) is initiated when DSBs are detected, leading to DNA break repair by non-homologous end joining (NHEJ). Read More

    BCL6 Overexpression Alters Gene Expression Profile in a Myeloma Cell Line and Is Associated with Decreased DNA Damage Response.
    Cancer Sci 2017 May 23. Epub 2017 May 23.
    Department of Medicine and Clinical Science, Gunma University Graduate School of Medicine, Gunma, Japan.
    BCL6 attenuates DNA damage response (DDR) through gene repression and facilitates tolerance to genomic instability during immunoglobulin affinity maturation in germinal center (GC) B cells. Although BCL6 expression is repressed through normal differentiation of GC B cells into plasma cells, a recent study showed the ectopic expression of BCL6 in primary multiple myeloma (MM) cells. However, the functional roles of BCL6 in MM cells are largely unknown. Read More

    Neurodegeneration in ataxia-telangiectasia: Multiple roles of ATM kinase in cellular homeostasis.
    Dev Dyn 2017 May 22. Epub 2017 May 22.
    School of Natural Sciences, Griffith University, Brisbane, Queensland, Australia.
    Ataxia-telangiectasia (A-T) is characterized by neuronal degeneration, cancer, diabetes, immune deficiency, and increased sensitivity to ionizing radiation. A-T is attributed to the deficiency of the protein kinase coded by the ATM (ataxia-telangiectasia mutated) gene. ATM is a sensor of DNA double-strand breaks (DSBs) and signals to cell cycle checkpoints and the DNA repair machinery. Read More

    Implications for breast cancer treatment from increased autotaxin production in adipose tissue after radiotherapy.
    FASEB J 2017 May 24. Epub 2017 May 24.
    Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada;
    We have previously established that adipose tissue adjacent to breast tumors becomes inflamed by tumor-derived cytokines. This stimulates autotaxin (ATX) secretion from adipocytes, whereas breast cancer cells produce insignificant ATX. Lysophosphatidate produced by ATX promotes inflammatory cytokine secretion in a vicious inflammatory cycle, which increases tumor growth and metastasis and decreases response to chemotherapy. Read More

    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 Jul 9;69(7):415-419. 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

    1 OF 176