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    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 Breakage Repair Disorders.
    J Allergy Clin Immunol 2017 Apr 6. Epub 2017 Apr 6.
    Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK; Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK. Electronic address:
    Background: Rare DNA breakage-repair disorders predispose to infection and lympho-reticular malignancies. Hematopoietic cell transplantation (HCT) is curative but co-administered chemo- or radio-therapy is damaging due to systemic radio-sensitivity. We collected HCT outcome data for Nijmegen Breakage syndrome (NBS), DNA ligase IV deficiency (LIG4), Cernunnos-XLF deficiency and ataxia-telangiectasia. 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

    Feedback regulation of methyl methanesulfonate and ultraviolet-sensitive gene clone 81 via ATM/Chk2 pathway contributes to the resistance of MCF-7 breast cancer cells to cisplatin.
    Tumour Biol 2017 Mar;39(3):1010428317694307
    1 Department of Clinical Laboratory Center, Shaoxing People's Hospital, Shaoxing Hospital of Zhejiang University, Shaoxing, Zhejiang, P.R. China.
    The methyl methanesulfonate and ultraviolet-sensitive gene clone 81 protein is a structure-specific nuclease that plays important roles in DNA replication and repair. Knockdown of methyl methanesulfonate and ultraviolet-sensitive gene clone 81 has been found to sensitize cancer cells to chemotherapy. However, the underlying molecular mechanism is not well understood. Read More

    Chemical screening identifies ATM as a target for alleviating senescence.
    Nat Chem Biol 2017 Mar 27. Epub 2017 Mar 27.
    Well Aging Research Center, DGIST, Daegu, Korea.
    Senescence, defined as irreversible cell-cycle arrest, is the main driving force of aging and age-related diseases. Here, we performed high-throughput screening to identify compounds that alleviate senescence and identified the ataxia telangiectasia mutated (ATM) inhibitor KU-60019 as an effective agent. To elucidate the mechanism underlying ATM's role in senescence, we performed a yeast two-hybrid screen and found that ATM interacted with the vacuolar ATPase V1 subunits ATP6V1E1 and ATP6V1G1. Read More

    The ATM kinase inhibitor KU-55933 provides neuroprotection against hydrogen peroxide-induced cell damage via a γH2AX/p-p53/caspase-3-independent mechanism: Inhibition of calpain and cathepsin D.
    Int J Biochem Cell Biol 2017 Mar 21;87:38-53. Epub 2017 Mar 21.
    Institute of Pharmacology, Polish Academy of Sciences, Department of Experimental Neuroendocrinology, Smętna Street 12, 31-343 Kraków, Poland.
    The role of the kinase ataxia-telangiectasia mutated (ATM), a well-known protein engaged in DNA damage repair, in the regulation of neuronal responses to oxidative stress remains unexplored. Thus, the neuroprotective efficacy of KU-55933, a potent inhibitor of ATM, against cell damage evoked by oxidative stress (hydrogen peroxide, H2O2) has been studied in human neuroblastoma SH-SY5Y cells and compared with the efficacy of this agent in models of doxorubicin (Dox)- and staurosporine (St)-evoked cell death. KU-55933 inhibited the cell death induced by H2O2 or Dox but not by St in undifferentiated (UN-) and retinoic acid-differentiated (RA)-SH-SY5Y cells, with a more pronounced effect in the latter cell phenotype. Read More

    Ataxia-telangiectasia: recommendations for multidisciplinary treatment.
    Dev Med Child Neurol 2017 Mar 20. Epub 2017 Mar 20.
    Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands.
    Ataxia-telangiectasia is a rare, neurodegenerative, and multisystem disease, characterized by cerebellar ataxia, oculocutaneous telangiectasia, immunodeficiency, progressive respiratory failure, and an increased risk of malignancies. It demands specialized care tailored to the individual patient's needs. Besides the classic ataxia-telangiectasia phenotype, a variant phenotype exists with partly overlapping but some distinctive disease characteristics. Read More

    Incidence of typically Severe Primary Immunodeficiency Diseases in Consanguineous and Non-consanguineous Populations.
    J Clin Immunol 2017 Apr 16;37(3):295-300. Epub 2017 Mar 16.
    Soroka University Medical Center, 84101, Beer-Sheva, Israel.
    Purpose: Primary immunodeficiency diseases are considered to be rare diseases; however, data on the exact birth incidences of these diseases are sparse. Southern Israel is inhabited by two major populations: a relatively non-consanguineous Jewish population and a highly consanguineous Muslim Bedouin population. We sought to calculate the incidences of typically severe primary immunodeficiency diseases and compare the incidences in these populations. Read More

    TP53 and ATM mRNA expression in skin and skeletal muscle after low-level laser exposure.
    J Cosmet Laser Ther 2017 Feb 16:1-5. Epub 2017 Feb 16.
    a Departamento de Ciências Fisiológicas , Instituto Biomédico, Universidade Federal do Estado do Rio de Janeiro , Rio de Janeiro , Brazil.
    Low-level lasers are widespread in regenerative medicine, but the molecular mechanisms involved in their biological effects are not fully understood, particularly those on DNA stability. Therefore, this study aimed to investigate mRNA expression of genes related to DNA genomic stability in skin and skeletal muscle tissue from Wistar rats exposed to low-level red and infrared lasers. For this, TP53 (Tumor Protein 53) and ATM (Ataxia Telangiectasia Mutated gene) mRNA expressions were evaluated by real-time quantitative PCR (RT-qPCR) technique 24 hours after low-level red and infrared laser exposure. Read More

    Quantitative and Dynamic Imaging of ATM Kinase Activity.
    Methods Mol Biol 2017 ;1596:131-145
    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

    Ataxia Oculomotor Apraxia Type 1 in the Siblings of a Family: A Novel Mutation.
    Iran J Child Neurol 2017 ;11(1):78-81
    Pediatric Neurology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran ; Pediatric Neurology Department, Mofid Children's Hospital, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
    Although AOA1 (ataxia oculomotor apraxia1) is one of the most common causes of autosomal recessive cerebellar ataxias in Japanese population, it is reported from all over the world. The clinical manifestations are similar to ataxia telangiectasia in which non-neurological manifestations are absent and include almost 10% of autosomal recessive cerebellar ataxias. Dysarthria and gait disorder are the most two common and typical manifestations. Read More

    Endosulfan induces cell dysfunction through cycle arrest resulting from DNA damage and DNA damage response signaling pathways.
    Sci Total Environ 2017 Jul 6;589:97-106. Epub 2017 Mar 6.
    Department of Toxicology and Hygienic Chemistry, School of Public Health, Capital Medical University, 100069 Beijing, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China.
    Our previous study showed that endosulfan increases the risk of cardiovascular disease. To identify toxic mechanism of endosulfan, we conducted an animal study for which 32 male Wistar rats were randomly and equally divided into four groups: Control group (corn oil only) and three treatment groups (1, 5 and 10mgkg(-1)·d(-1)). The results showed that exposure to endosulfan resulted in injury of cardiac tissue with impaired mitochondria integrity and elevated 8-OHdG expression in myocardial cells. Read More

    DNA damage response is hijacked by human papillomaviruses to complete their life cycle.
    J Zhejiang Univ Sci B 2017 Mar.;18(3):215-232
    Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
    The DNA damage response (DDR) is activated when DNA is altered by intrinsic or extrinsic agents. This pathway is a complex signaling network and plays important roles in genome stability, tumor transformation, and cell cycle regulation. Human papillomaviruses (HPVs) are the main etiological agents of cervical cancer. Read More

    Parvovirus B19 NS1 protein induces cell cycle arrest at G2-phase by activating the ATR-CDC25C-CDK1 pathway.
    PLoS Pathog 2017 Mar 6;13(3):e1006266. Epub 2017 Mar 6.
    Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City, Kansas, United States of America.
    Human parvovirus B19 (B19V) infection of primary human erythroid progenitor cells (EPCs) arrests infected cells at both late S-phase and G2-phase, which contain 4N DNA. B19V infection induces a DNA damage response (DDR) that facilitates viral DNA replication but is dispensable for cell cycle arrest at G2-phase; however, a putative C-terminal transactivation domain (TAD2) within NS1 is responsible for G2-phase arrest. To fully understand the mechanism underlying B19V NS1-induced G2-phase arrest, we established two doxycycline-inducible B19V-permissive UT7/Epo-S1 cell lines that express NS1 or NS1mTAD2, and examined the function of the TAD2 domain during G2-phase arrest. Read More

    RUG3 and ATM synergistically regulate the alternative splicing of mitochondrial nad2 and the DNA damage response in Arabidopsis thaliana.
    Sci Rep 2017 Mar 6;7:43897. Epub 2017 Mar 6.
    State Key Laboratory of Agricultural Microbiology, College of Plant Science and Technology Huazhong Agricultural University, Wuhan 430070, P.R. China.
    The root apical meristem (RAM) determines both RAM activity and the growth of roots. Plant roots are constantly exposed to adverse environmental stresses that can cause DNA damage or cell cycle arrest in the RAM; however, the mechanism linking root meristematic activity and RAM size to the DNA damage response (DDR) is unclear. Here, we demonstrate that a loss of function in RCC1/UVR8/GEF-Like 3 (RUG3) substantially augmented the DDR and produced a cell cycle arrest in the RAM in rug3 mutant, leading to root growth retardation. Read More

    The impact of oxidative DNA changes and ATM expression on morphological and functional activities on hepatocytes obtained from mesenchymal stem cells.
    Biologicals 2017 Mar 3. Epub 2017 Mar 3.
    Department of Bioresource Engineering, Faculty of Agricultural and Environmental Sciences, Quebec, H9X 3V9, Canada.
    Resistance to oxidative damages in undifferentiated mesenchymal stem cells (MSCs) in comparison with the undifferentiated progenitor cells may differ depending on several factors. This study was carried out to examine the impact of hepatogenic differentiation process of MSCs on oxidative DNA damage markers. Hepatic differentiation of MSCs was carried out using a two-step conventional protocol and the cells were processed for characterization using morphological and biochemical markers. Read More

    Mechanisms of Non-canonical Activation of Ataxia Telangiectasia Mutated.
    Biochemistry (Mosc) 2016 Dec;81(13):1669-1675
    University of Cambridge, Department of Biochemistry, Cambridge, CB2 1GA, UK.
    ATM is a master regulator of the cellular response to DNA damage. The classical mechanism of ATM activation involves its monomerization in response to DNA double-strand breaks, resulting in ATM-dependent phosphorylation of more than a thousand substrates required for cell cycle progression, DNA repair, and apoptosis. Here, new experimental evidence for non-canonical mechanisms of ATM activation in response to stimuli distinct from DNA double-strand breaks is discussed. Read More

    miR-30a radiosensitizes non-small cell lung cancer by targeting ATF1 that is involved in the phosphorylation of ATM.
    Oncol Rep 2017 Apr 14;37(4):1980-1988. Epub 2017 Feb 14.
    Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
    Increasing number of studies report that microRNAs play important roles in radiosensitization. miR-30a has been proved to perform many functions in the development and treatment of cancer, and it is downregulated in non-small cell lung cancer (NSCLC) tissues and cells. This study was conducted to understand if miR-30a plays a role in the radiosensitivity of NSCLC cells. Read More

    Combined metabolic and transcriptional profiling identifies pentose phosphate pathway activation by HSP27 phosphorylation during cerebral ischemia.
    Neuroscience 2017 May 6;349:1-16. Epub 2017 Mar 6.
    Department of Neurosurgery, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
    The metabolic pathophysiology underlying ischemic stroke remains poorly understood. To gain insight into these mechanisms, we performed a comparative metabolic and transcriptional analysis of the effects of cerebral ischemia on the metabolism of the cerebral cortex using middle cerebral artery occlusion (MCAO) rat model. Metabolic profiling by gas-chromatography/mass-spectrometry analysis showed clear separation between the ischemia and control group. Read More

    Chloroquine triggers Epstein-Barr virus replication through phosphorylation of KAP1/TRIM28 in Burkitt lymphoma cells.
    PLoS Pathog 2017 Mar 1;13(3):e1006249. Epub 2017 Mar 1.
    Division of Infectious Diseases, Department of Pediatrics, Stony Brook University School of Medicine, Stony Brook, NY, United States of America.
    Trials to reintroduce chloroquine into regions of Africa where P. falciparum has regained susceptibility to chloroquine are underway. However, there are long-standing concerns about whether chloroquine increases lytic-replication of Epstein-Barr virus (EBV), thereby contributing to the development of endemic Burkitt lymphoma. Read More

    TIRR regulates 53BP1 by masking its histone methyl-lysine binding function.
    Nature 2017 Mar 27;543(7644):211-216. Epub 2017 Feb 27.
    Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
    P53-binding protein 1 (53BP1) is a multi-functional double-strand break repair protein that is essential for class switch recombination in B lymphocytes and for sensitizing BRCA1-deficient tumours to poly-ADP-ribose polymerase-1 (PARP) inhibitors. Central to all 53BP1 activities is its recruitment to double-strand breaks via the interaction of the tandem Tudor domain with dimethylated lysine 20 of histone H4 (H4K20me2). Here we identify an uncharacterized protein, Tudor interacting repair regulator (TIRR), that directly binds the tandem Tudor domain and masks its H4K20me2 binding motif. Read More

    Screening of gene mutations associated with bone metastasis in nonsmall cell lung cancer.
    J Cancer Res Ther 2016 Dec;12(Supplement):C186-C190
    Department of Lung Cancer, The Affiliated Hospital of Military Medical Sciences, The 307th Hospital of Chinese People's Liberation Army, Beijing, China.
    Objective: The objective of this study is to assess the gene mutation of advanced nonsmall cell lung cancer (NSCLC) patients with bone metastasis using next-generation sequencing (NGS), and screen for the driver genes which are associated with bone metastasis of lung cancer.

    Materials And Methods: Eight clinicopathologic samples from advanced NSCLC combined with bone metastasis patients were collected. Exome sequencing was conducted within 483 tumor-associated genes using Hiseq 2000_PE75 NGS platform. Read More

    Targeting DNA Damage Response in Prostate Cancer by Inhibiting Androgen Receptor-CDC6-ATR-Chk1 Signaling.
    Cell Rep 2017 Feb;18(8):1970-1981
    Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address:
    Cell division cycle 6 (CDC6), an androgen receptor (AR) target gene, is implicated in regulating DNA replication and checkpoint mechanisms. CDC6 expression is increased during prostate cancer (PCa) progression and positively correlates with AR in PCa tissues. AR or CDC6 knockdown, together with AZD7762, a Chk1/2 inhibitor, results in decreased TopBP1-ATR-Chk1 signaling and markedly increased ataxia-telangiectasia-mutated (ATM) phosphorylation, a biomarker of DNA damage, and synergistically increases treatment efficacy. Read More

    The p53-binding protein 1-Tudor-interacting repair regulator complex participates in the DNA damage response.
    J Biol Chem 2017 Apr 17;292(16):6461-6467. Epub 2017 Feb 17.
    From the Department of Cancer Biology, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio 44195 and
    The 53BP1-dependent end-joining pathway plays a critical role in double strand break repair and is uniquely responsible for cellular sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPi) in BRCA1-deficient cancers. We and others have investigated the downstream effectors of 53BP1, including replication timing regulatory factor 1 (RIF1) and Pax transactivation domain-interacting protein (PTIP), in the past few years to elucidate how loss of the 53BP1-dependent repair pathway results in PARPi resistance in BRCA1 patients. However, questions regarding the upstream regulation of the 53BP1 pathway remain unanswered. Read More

    Immature Lymphocytes Inhibit Rag1 and Rag2 Transcription and V(D)J Recombination in Response to DNA Double-Strand Breaks.
    J Immunol 2017 Apr 17;198(7):2943-2956. Epub 2017 Feb 17.
    Division of Cancer Pathobiology, Department of Pathology and Laboratory Medicine, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104;
    Mammalian cells have evolved a common DNA damage response (DDR) that sustains cellular function, maintains genomic integrity, and suppresses malignant transformation. In pre-B cells, DNA double-strand breaks (DSBs) induced at Igκ loci by the Rag1/Rag2 (RAG) endonuclease engage this DDR to modulate transcription of genes that regulate lymphocyte-specific processes. We previously reported that RAG DSBs induced at one Igκ allele signal through the ataxia telangiectasia mutated (ATM) kinase to feedback-inhibit RAG expression and RAG cleavage of the other Igκ allele. Read More

    The DNA damage response promotes polyomavirus JC infection by nucleus to cytoplasm NF- kappaB activation.
    Virol J 2017 Feb 15;14(1):31. Epub 2017 Feb 15.
    Center for Neurovirology, Department of Neuroscience, Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA, 19140, USA.
    Background: Infection of glial cells by human neurotropic polyomavirus JC (JCV), the causative agent of the CNS demyelinating disease progressive multifocal leukoencephalopathy (PML), rapidly inflicts damage to cellular DNA. This activates DNA damage response (DDR) signaling including induction of expression of DNA repair factor Rad51. We previously reported that Rad51 co-operates with the transcription factor NF-κB p65 to activate JCV early transcription. Read More

    Genomic profiling of Acute lymphoblastic leukemia in ataxia telangiectasia patients reveals tight link between ATM mutations and chromothripsis.
    Leukemia 2017 Mar 14. Epub 2017 Mar 14.
    Division of Molecular Genetics, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Recent developments in sequencing technologies led to the discovery of a novel form of genomic instability, termed chromothripsis. This catastrophic genomic event, involved in tumorigenesis, is characterized by tens to hundreds of simultaneously acquired locally clustered rearrangements on one chromosome. We hypothesized that leukemias developing in individuals with Ataxia Telangiectasia, who are born with two mutated copies of the ATM gene, an essential guardian of genome stability, would show a higher prevalence of chromothripsis due to the associated defect in DNA double-strand break repair. Read More

    FANCD2 Binds Human Papillomavirus Genomes and Associates with a Distinct Set of DNA Repair Proteins to Regulate Viral Replication.
    MBio 2017 Feb 14;8(1). Epub 2017 Feb 14.
    Department of Microbiology-Immunology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA
    The life cycle of human papillomavirus (HPV) is dependent on the differentiation state of its host cell. HPV genomes are maintained as low-copy episomes in basal epithelial cells and amplified to thousands of copies per cell in differentiated layers. Replication of high-risk HPVs requires the activation of the ataxia telangiectasia-mutated (ATM) and ATM and Rad3-related (ATR) DNA repair pathways. Read More

    Inhibiting DNA-PKcs in a non-homologous end-joining pathway in response to DNA double-strand breaks.
    Oncotarget 2017 Apr;8(14):22662-22673
    Department of Radiation Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
    DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a distinct factor in the non-homologous end-joining (NHEJ) pathway involved in DNA double-strand break (DSB) repair. We examined the crosstalk between key proteins in the DSB NHEJ repair pathway and cell cycle regulation and found that mouse embryonic fibroblast (MEF) cells deficient in DNA-PKcs or Ku70 were more vulnerable to ionizing radiation (IR) compared with wild-type cells and that DSB repair was delayed. γH2AX was associated with phospho-Ataxia-telangiectasia mutated kinase (Ser1987) and phospho-checkpoint effector kinase 1 (Ser345) foci for the arrest of cell cycle through the G2/M phase. Read More

    RECQ1 helicase is involved in replication stress survival and drug resistance in multiple myeloma.
    Leukemia 2017 Mar 10. Epub 2017 Mar 10.
    Institute of Human Genetics, UMR 9002, CNRS and University of Montpellier, Montpellier, France.
    Multiple myeloma (MM) is a plasma cell cancer with poor survival, characterized by the expansion of multiple myeloma cells (MMCs) in the bone marrow. Using a microarray-based genome-wide screen for genes responding to DNA methyltransferases (DNMT) inhibition in MM cells, we identified RECQ1 among the most downregulated genes. RecQ helicases are DNA unwinding enzymes involved in the maintenance of chromosome stability. Read More

    ATM-Deficient Colorectal Cancer Cells Are Sensitive to the PARP Inhibitor Olaparib.
    Transl Oncol 2017 Apr 6;10(2):190-196. Epub 2017 Feb 6.
    Department of Biochemistry & Molecular Biology, Robson DNA Science Centre, Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada; Department on Oncology, Tom Baker Cancer Centre, Calgary, Alberta, Canada. Electronic address:
    The ataxia telangiectasia mutated (ATM) protein kinase plays a central role in the cellular response to DNA damage. Loss or inactivation of both copies of the ATM gene (ATM) leads to ataxia telangiectasia, a devastating childhood condition characterized by neurodegeneration, immune deficiencies, and cancer predisposition. ATM is also absent in approximately 40% of mantle cell lymphomas (MCLs), and we previously showed that MCL cell lines with loss of ATM are sensitive to poly-ADP ribose polymerase (PARP) inhibitors. Read More

    The Clinical Significance of Complete Class Switching Defect in Ataxia Telangiectasia Patients.
    Expert Rev Clin Immunol 2017 Feb 4. Epub 2017 Feb 4.
    a Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center , Tehran University of Medical Sciences , Tehran , Iran.
    Objectives: Ataxia telangiectasia (AT) is a primary immunodeficiency associated with recurrent infections. We aimed to investigate clinical and immunological classification in AT patients who suffer from a different spectrum of humoral immune defects.

    Methods: AT patients were categorized according to the ability of class switching and patients with hyper IgM (HIgM) profile were defined as class switching defect (CSD). Read More

    Evaluation of [(18)F]-ATRi as PET tracer for in vivo imaging of ATR in mouse models of brain cancer.
    Nucl Med Biol 2017 May 16;48:9-15. Epub 2017 Jan 16.
    Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA; Weill Cornell Medical College, New York, NY, 10065, USA. Electronic address:
    Rationale: Ataxia telangiectasia and Rad3-related (ATR) threonine serine kinase is one of the key elements in orchestrating the DNA damage response (DDR). As such, inhibition of ATR can amplify the effects of chemo- and radiation-therapy, and several ATR inhibitors (ATRi) have already undergone clinical testing in cancer. For more accurate patient selection, monitoring and staging, real-time in vivo imaging of ATR could be invaluable; the development of appropriate imaging agents has remained a major challenge. Read More

    RAD54 forms DNA repair foci in response to DNA damage in living plant cells.
    Plant J 2017 Apr 25;90(2):372-382. Epub 2017 Mar 25.
    Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba, 278-8510, Japan.
    Plants have various defense mechanisms against environmental stresses that induce DNA damage. Genetic and biochemical analyses have revealed the sensing and signaling of DNA damage, but little is known about subnuclear dynamics in response to DNA damage in living plant cells. Here, we observed that the chromatin remodeling factor RAD54, which is involved in DNA repair via the homologous recombination pathway, formed subnuclear foci (termed RAD54 foci) in Arabidopsis thaliana after induction of DNA double-strand breaks. Read More

    AZD6738, A Novel Oral Inhibitor of ATR, Induces Synthetic Lethality with ATM Deficiency in Gastric Cancer Cells.
    Mol Cancer Ther 2017 Apr 30;16(4):566-577. Epub 2017 Jan 30.
    Cancer Research Institute, Seoul National University, Seoul, Korea.
    Ataxia telangiectasia and Rad3-related (ATR) can be considered an attractive target for cancer treatment due to its deleterious effect on cancer cells harboring a homologous recombination defect. The aim of this study was to investigate the potential use of the ATR inhibitor, AZD6738, to treat gastric cancer.In SNU-601 cells with dysfunctional ATM, AZD6738 treatment led to an accumulation of DNA damage due to dysfunctional RAD51 foci formation, S phase arrest, and caspase 3-dependent apoptosis. Read More

    Discovery of pyrazolopyrimidine derivatives as novel inhibitors of ataxia telangiectasia and rad3 related protein (ATR).
    Bioorg Med Chem Lett 2017 Feb 16;27(4):750-754. Epub 2017 Jan 16.
    Medivation, Now Pfizer Inc., 525 Market Street, 36th Floor, San Francisco, CA 94105, United States. Electronic address:
    The ATR pathway is a critical mediator of the replication stress response in cells. In aberrantly proliferating cancer cells, this pathway can help maintain sufficient genomic integrity for cancer cell progression. Herein we describe the discovery of 19, a pyrazolopyrimidine-containing inhibitor of ATR via a strategic repurposing of compounds targeting PI3K. Read More

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