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    CTCF prevents genomic instability by promoting homologous recombination-directed DNA double-strand break repair.
    Proc Natl Acad Sci U S A 2017 Oct 25;114(41):10912-10917. Epub 2017 Sep 25.
    Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China;
    CTCF is an essential epigenetic regulator mediating chromatin insulation, long-range regulatory interactions, and the organization of large topological domains in the nucleus. Phenotypes of CTCF haploinsufficient mutations in humans, knockout in mice, and depletion in cells are often consistent with impaired genome stability, but a role of CTCF in genome maintenance has not been fully investigated. Here, we report that CTCF maintains genome stability, is recruited to sites of DNA damage, and promotes homologous recombination repair of DNA double-strand breaks (DSBs). Read More

    Clinical Report: Warsaw Breakage Syndrome with small radii and fibulae.
    Am J Med Genet A 2017 Nov 28;173(11):3075-3081. Epub 2017 Sep 28.
    Division of Genetics, Department of Pediatrics, University of California, San Francisco, California.
    We present two new cases of Warsaw Breakage Syndrome (WABS), an autosomal recessive cohesinopathy, in sisters aged 13 and 11 years who both had compound heterozygous mutations in DDX11. After exclusion of Fanconi anemia, Bloom syndrome and Nijmegen breakage syndrome, whole exome sequencing revealed two novel variants-c.1523T>G, predicting (p. Read More

    MRE11 Promotes Tumorigenesis by Facilitating Resistance to Oncogene-Induced Replication Stress.
    Cancer Res 2017 Oct 17;77(19):5327-5338. Epub 2017 Aug 17.
    Department of Pathology, The University of Michigan Medical School, Ann Arbor, Michigan.
    Hypomorphic mutations in the genes encoding the MRE11/RAD50/NBS1 (MRN) DNA repair complex lead to cancer-prone syndromes. MRN binds DNA double-strand breaks, where it functions in repair and triggers cell-cycle checkpoints via activation of the ataxia-telangiectasia mutated kinase. To gain understanding of MRN in cancer, we engineered mice with B lymphocytes lacking MRN, or harboring MRN in which MRE11 lacks nuclease activities. Read More

    Prospective Study of a Cohort of Russian Nijmegen Breakage Syndrome Patients Demonstrating Predictive Value of Low Kappa-Deleting Recombination Excision Circle (KREC) Numbers and Beneficial Effect of Hematopoietic Stem Cell Transplantation (HSCT).
    Front Immunol 2017 24;8:807. Epub 2017 Jul 24.
    Dmitry Rogachev National Research and Clinical Center for Pediatric Hematology, Oncology and Immunology, Moscow, Russia.
    Background: Nijmegen breakage syndrome (NBS) is a combined primary immunodeficiency with DNA repair defect, microcephaly, and other phenotypical features. It predominantly occurs in Slavic populations that have a high frequency of carriers with the causative NBN gene c.657_661del5 mutation. Read More

    Nijmegen Breakage Syndrome fibroblasts and iPSCs: cellular models for uncovering disease-associated signaling pathways and establishing a screening platform for anti-oxidants.
    Sci Rep 2017 Aug 8;7(1):7516. Epub 2017 Aug 8.
    Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich Heine University, 40225, Düsseldorf, Germany.
    Nijmegen Breakage Syndrome (NBS) is associated with cancer predisposition, premature aging, immune deficiency, microcephaly and is caused by mutations in the gene coding for NIBRIN (NBN) which is involved in DNA damage repair. Dermal-derived fibroblasts from NBS patients were reprogrammed into induced pluripotent stem cells (iPSCs) in order to bypass premature senescence. The influence of antioxidants on intracellular levels of ROS and DNA damage were screened and it was found that EDHB-an activator of the hypoxia pathway, decreased DNA damage in the presence of high oxidative stress. Read More

    Effects of Pulsed Electromagnetic Fields on Breast Cancer Cell Line MCF 7 Using Absorption Spectroscopy.
    Anticancer Res 2017 07;37(7):3453-3459
    Faculty of Science, Liverpool Hope University, Liverpool, U.K.
    We present an analysis of the effects of pulsed electromagnetic fields (PEMF) with 3.3 MHz carrier frequency and modulated by audio resonant frequencies on the MCF-7 breast cancer cell line in vitro using absorption spectroscopy. This involves a fluorescence dye called PrestoBlue™ Cell Viability Reagent and a spectrophotometry to test the viability of MCF-7 breast cancer cells under different PEMF treatment conditions in terms of the cell absorption values. Read More

    Cancer predisposition syndromes associated with myeloid malignancy.
    Semin Hematol 2017 Apr 7;54(2):115-122. Epub 2017 Apr 7.
    Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN. Electronic address:
    The majority of myeloid malignancies are caused by sporadic somatic events rather than cancer predisposition. Nonetheless, the identification of hereditary cancer predisposition syndromes is critical when caring for patients with myeloid malignancies since detection may direct decisions related to cancer treatment and surveillance. A positive genetic test result also has important implications for other family members who can use this information to undergo their own testing to determine their cancer risk. Read More

    Hsp90α regulates ATM and NBN functions in sensing and repair of DNA double-strand breaks.
    FEBS J 2017 Aug 9;284(15):2378-2395. Epub 2017 Jul 9.
    Department of Sciences, Roma Tre University, Roma, Italy.
    The molecular chaperone heat shock protein 90 (Hsp90α) regulates cell proteostasis and mitigates the harmful effects of endogenous and exogenous stressors on the proteome. Indeed, the inhibition of Hsp90α ATPase activity affects the cellular response to ionizing radiation (IR). Although the interplay between Hsp90α and several DNA damage response (DDR) proteins has been reported, its role in the DDR is still unclear. 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

    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

    Contribution of Double-strand Break Repair Gene Nijmegen Breakage Syndrome 1 Genotypes, Gender Difference and Smoking Status to Taiwanese Lung Cancer.
    Anticancer Res 2017 05;37(5):2417-2423
    Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, R.O.C.
    Background/aim: Nijmegen breakage syndrome 1 (NBS1) is a component of MRE11/RAD50/NBS1 complex (MRN) that plays a critical role in the cellular response to DNA damage and maintenance of chromosomal integrity. Failure in DNA damage response affects the level of cell survival, increases the frequency of gene mutation or chromosomal instability and other cellular phenotypic abnormalities, which are the important mechanisms of carcinogenesis. However, the contribution of variant NBS1 genotypes to lung cancer is not known. Read More

    Parkin regulates translesion DNA synthesis in response to UV radiation.
    Oncotarget 2017 May;8(22):36423-36437
    State Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100101, China.
    Deficiency of Parkin is a major cause of early-onset Parkinson's disease (PD). Notably, PD patients also exhibit a significantly higher risk in melanoma and other skin tumors, while the mechanism remains largely unknown. In this study, we show that depletion of Parkin causes compromised cell viability and genome stability after ultraviolet (UV) radiation. 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

    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 Jul;58(4):487-494
    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

    Stimulation of lactate receptor (HCAR1) affects cellular DNA repair capacity.
    DNA Repair (Amst) 2017 Apr 20;52:49-58. Epub 2017 Feb 20.
    Department of Molecular Cell Mechanisms, Medical University of Lodz, Poland.
    Numerous G-protein coupled receptors have been reported to enhance cancer cell survival and resistance to clinically used chemotherapeutics. Recently, hydroxycarboxylic acid receptor 1 (HCAR1) was shown to drive lactate-dependent enhancement of cell survival and metastasis in pancreatic and breast cancers. Furthermore, our previous study confirmed the involvement of HCAR1 in lactate-related enhancement of DNA repair in cervical cancer cells. Read More

    NBS1 Phosphorylation Status Dictates Repair Choice of Dysfunctional Telomeres.
    Mol Cell 2017 Mar 16;65(5):801-817.e4. Epub 2017 Feb 16.
    Department of Laboratory Medicine, Yale University School of Medicine, 330 Cedar Street, New Haven, CT 06520, USA; Department of Pathology, Yale University School of Medicine, 330 Cedar Street, New Haven, CT 06520, USA; Molecular Biophysics and Biochemistry, Yale University School of Medicine, 330 Cedar Street, New Haven, CT 06520, USA. Electronic address:
    Telomeres employ TRF2 to protect chromosome ends from activating the DNA damage sensor MRE11-RAD50-NBS1 (MRN), thereby repressing ATM-dependent DNA damage checkpoint responses. How TRF2 prevents MRN activation at dysfunctional telomeres is unclear. Here, we show that the phosphorylation status of NBS1 determines the repair pathway choice of dysfunctional telomeres. Read More

    Case report: rapid and durable response to PDGFR targeted therapy in a child with refractory multiple infantile myofibromatosis and a heterozygous germline mutation of the PDGFRB gene.
    BMC Cancer 2017 Feb 10;17(1):119. Epub 2017 Feb 10.
    Department of Pediatric Oncology, University Hospital Brno and School of Medicine, Masaryk University, Cernopolni 9, Brno, 613 00, Czech Republic.
    Background: Infantile myofibromatosis belongs to a family of soft tissue tumors. The majority of these tumors have benign behavior but resistant and malignant courses are known, namely in tumors with visceral involvement. The standard of care is surgical resection. Read More

    An Approach to Elucidate NBS1 Function in DNA Repair Using Frequent Nonsynonymous Polymorphism in Wild Medaka (Oryzias latipes) Populations.
    PLoS One 2017 20;12(1):e0170006. Epub 2017 Jan 20.
    Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Japan.
    Nbs1 is one of the genes responsible for Nijmegen breakage syndrome, which is marked with high radiosensitivity. In human NBS1 (hNBS1), Q185E polymorphism is known as the factor to cancer risks, although its DSB repair defect has not been addressed. Here we investigated the genetic variations in medaka (Oryzias latipes) wild populations, and found 40 nonsynonymous single nucleotide polymorphisms (SNPs) in medaka nbs1 (olnbs1) gene within 5 inbred strains. Read More

    Oxidative stress, mitochondrial abnormalities and antioxidant defense in Ataxia-telangiectasia, Bloom syndrome and Nijmegen breakage syndrome.
    Redox Biol 2017 Apr 28;11:375-383. Epub 2016 Dec 28.
    Department of Experimental Pharmacology, Medical University of Bialystok, Szpitalna 37 Str., 15-295 Bialystok, Poland. Electronic address:
    Rare pleiotropic genetic disorders, Ataxia-telangiectasia (A-T), Bloom syndrome (BS) and Nijmegen breakage syndrome (NBS) are characterised by immunodeficiency, extreme radiosensitivity, higher cancer susceptibility, premature aging, neurodegeneration and insulin resistance. Some of these functional abnormalities can be explained by aberrant DNA damage response and chromosomal instability. It has been suggested that one possible common denominator of these conditions could be chronic oxidative stress caused by endogenous ROS overproduction and impairment of mitochondrial homeostasis. Read More

    Circulating T Cells of Patients with Nijmegen Breakage Syndrome Show Signs of Senescence.
    J Clin Immunol 2017 Feb 21;37(2):133-142. Epub 2016 Dec 21.
    Department of Immunology, Laboratory for Medical Immunology, Erasmus MC, University Medical Center Rotterdam, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands.
    Purpose: The Nijmegen breakage syndrome (NBS) is an inherited genetic disorder characterized by a typical facial appearance, microcephaly, growth retardation, immunodeficiency, and a strong predisposition to malignancies, especially of lymphoid origin. NBS patients have a mutation in the NBN gene which involves the repair of DNA double-strand breaks (DSBs). Here we studied the peripheral T cell compartment of NBS patients with a focus on immunological senescence. Read More

    The Slavic NBN Founder Mutation: A Role for Reproductive Fitness?
    PLoS One 2016 9;11(12):e0167984. Epub 2016 Dec 9.
    Cologne Center for Genomics, University of Cologne, Köln, Germany.
    The vast majority of patients with Nijmegen Breakage Syndrome (NBS) are of Slavic origin and carry a deleterious deletion (c.657del5; rs587776650) in the NBN gene on chromosome 8q21. This mutation is essentially confined to Slavic populations and may thus be considered a Slavic founder mutation. Read More

    Identification of a rare germline NBN gene mutation by whole exome sequencing in a lung-cancer survivor from a large family with various types of cancer.
    Fam Cancer 2017 Jul;16(3):389-394
    Department of Pathology, Faculty of Medicine, Kuwait University, P.O. Box 24923, 13110, Safat, Kuwait.
    Nijmegen breakage syndrome is an autosomal recessive disorder caused by biallelic mutation in NBN gene. It is characterized by microcephaly, growth retardation, immuno-deficiency and cancer predisposition. The monoallelic carriers of NBN gene are also reported to be at increased risk of developing various types of malignancy. Read More

    High Expression of MRE11-RAD50-NBS1 Is Associated with Poor Prognosis and Chemoresistance in Gastric Cancer.
    Anticancer Res 2016 10;36(10):5237-5247
    Department of General Surgical Science, Gunma University Graduate School of Medicine, Gunma, Japan.
    Background: The MRN complex of meiotic recombination 11 (MRE11), DNA repair protein Rad50 (RAD50) and Nijmegen breakage syndrome 1 (NBS1) proteins coordinate the detection and repair of DNA double-strand breaks (DSBs). DNA DSB repair-dependent chemoresistance likely has an effect on the treatment of human cancer.

    Materials And Methods: We investigated the expression of MRN complex in human gastric cancer (GC) tissues using immunohistochemistry and analyzed its clinical significance and prognostic relevance. Read More

    T-lymphoblastic leukemia/lymphoma in macedonian patients with Nijmegen breakage syndrome.
    Balkan J Med Genet 2016 Jul 2;19(1):91-94. Epub 2016 Aug 2.
    Center for Biomolecular Pharmaceutical Analyses, Faculty of Pharmacy, University "St. Cyril and Methodius," Skopje, Republic of Macedonia.
    Nijmegen breakage syndrome (NBS) is a rare autosomal recessive chromosomal instability disorder characterized by microcephaly, immunodeficiency, radiosensitivity and a very high predisposition to malignancy. The gene responsible for the disease, NBS1, is located on chromosome 8q21 and encodes a protein called nibrin. After identification of the gene, a truncating 5 bp deletion, 657-661delACAAA, was identified as the disease-causing mutation in patients with the NBS. Read More

    Chromosomal Instability and Molecular Defects in Induced Pluripotent Stem Cells from Nijmegen Breakage Syndrome Patients.
    Cell Rep 2016 Aug 18;16(9):2499-511. Epub 2016 Aug 18.
    Department of Genetics, Institute of Life Sciences, The Hebrew University, Givat-Ram, Jerusalem 91904, Israel. Electronic address:
    Nijmegen breakage syndrome (NBS) results from the absence of the NBS1 protein, responsible for detection of DNA double-strand breaks (DSBs). NBS is characterized by microcephaly, growth retardation, immunodeficiency, and cancer predisposition. Here, we show successful reprogramming of NBS fibroblasts into induced pluripotent stem cells (NBS-iPSCs). Read More

    Non-Hodgkin lymphoma and pre-existing conditions: spectrum, clinical characteristics and outcome in 213 children and adolescents.
    Haematologica 2016 Dec 11;101(12):1581-1591. Epub 2016 Aug 11.
    Pediatric Hematology and Oncology, University of Padova, Italy.
    Children and adolescents with pre-existing conditions such as DNA repair defects or other primary immunodeficiencies have an increased risk of non-Hodgkin lymphoma. However, large-scale data on patients with non-Hodgkin lymphoma and their entire spectrum of pre-existing conditions are scarce. A retrospective multinational study was conducted by means of questionnaires sent out to the national study groups or centers, by the two largest consortia in childhood non-Hodgkin lymphoma, the European Intergroup for Childhood non-Hodgkin Lymphoma, and the international Berlin-Frankfurt-Münster Study Group. Read More

    NBS1 and multiple regulations of DNA damage response.
    J Radiat Res 2016 Aug 10;57 Suppl 1:i11-i17. Epub 2016 Apr 10.
    Division of Genome Repair Dynamics, Radiation Biology Center, Kyoto University, Yoshida-Konoecho, Sakyo-Ku, Kyoto 606-8501, Japan
    DNA damage response is finely tuned, with several pathways including those for DNA repair, chromatin remodeling and cell cycle checkpoint, although most studies to date have focused on single pathways. Genetic diseases characterized by genome instability have provided novel insights into the underlying mechanisms of DNA damage response. NBS1, a protein responsible for the radiation-sensitive autosomal recessive disorder Nijmegen breakage syndrome, is one of the first factors to accumulate at sites of DNA double-strand breaks (DSBs). Read More

    Epidermal Nbn deletion causes premature hair loss and a phenotype resembling psoriasiform dermatitis.
    Oncotarget 2016 Apr;7(17):23006-18
    Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Nijmegen Breakage Syndrome is a disease caused by NBN mutations. Here, we report a novel function of Nbn in skin homeostasis. We found that Nbn deficiency in hair follicle (HF) progenitors promoted increased DNA damage signaling, stimulating p16Ink4a up-regulation, Trp53 stabilization and cytokines secretion leading to HF-growth arrest and hair loss. Read More

    The MRX Complex Ensures NHEJ Fidelity through Multiple Pathways Including Xrs2-FHA-Dependent Tel1 Activation.
    PLoS Genet 2016 Mar 18;12(3):e1005942. Epub 2016 Mar 18.
    Department of Integrated Protein Functions, Institute for Protein Research, Osaka University, Suita, Osaka, Japan.
    Because DNA double-strand breaks (DSBs) are one of the most cytotoxic DNA lesions and often cause genomic instability, precise repair of DSBs is vital for the maintenance of genomic stability. Xrs2/Nbs1 is a multi-functional regulatory subunit of the Mre11-Rad50-Xrs2/Nbs1 (MRX/N) complex, and its function is critical for the primary step of DSB repair, whether by homologous recombination (HR) or non-homologous end joining. In human NBS1, mutations result truncation of the N-terminus region, which contains a forkhead-associated (FHA) domain, cause Nijmegen breakage syndrome. Read More

    Generation of iPSC lines from a Nijmegen Breakage Syndrome patient.
    Stem Cell Res 2015 Nov 23;15(3):629-32. Epub 2015 Oct 23.
    Max Planck Institute for Molecular Genetics, 14195, Berlin, Germany; Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany. Electronic address:
    Human dermal fibroblasts from a Nijmegen Breakage Syndrome (NBS) patient bearing the 657del5 mutation within the DNA repair gene NIBRIN were used to generate two iPSC-lines (vNBS8-iPS-c1, vNBS8-iPS-c2) by retroviral transduction of OCT4, SOX2, c-MYC and KLF4. Pluripotency was confirmed both in vivo and in vitro. Read More

    Severe mitochondrial damage associated with low-dose radiation sensitivity in ATM- and NBS1-deficient cells.
    Cell Cycle 2016 ;15(8):1099-107
    a Department of Environmental Health , National Institute of Public Health , Wako , Saitama , Japan.
    Low-dose radiation risks remain unclear owing to a lack of sufficient studies. We previously reported that low-dose, long-term fractionated radiation (FR) with 0.01 or 0. Read More

    Clinical course and therapeutic implications for lymphoid malignancies in Nijmegen breakage syndrome.
    Eur J Med Genet 2016 Mar 27;59(3):126-32. Epub 2016 Jan 27.
    Department of Pediatrics, Hematology, Oncology and Diabetology, Medical University of Lodz, Poland. Electronic address:
    Nijmegen breakage syndrome (NBS, MIM #251260) is an autosomal recessive chromosomal instability disorder. Majority of patients affected are of Slavic origin and share the same founder mutation of 657del5 within the NBN gene encoding protein involved in DNA double-strand breaks repair. Clinically, this is characterized by a microcephaly, immunodeficiency and a high incidence of pediatric malignancies, mostly lymphomas and leukemias. Read More

    Preexisting conditions in pediatric ALL patients: Spectrum, frequency and clinical impact.
    Eur J Med Genet 2016 Mar 28;59(3):143-51. Epub 2015 Dec 28.
    Department of Pediatric Hematology and Oncology, Hanover Medical School, Germany.
    Introduction: The etiology of acute lymphoblastic leukemia remains undisclosed in the majority of cases. A number of rare syndromic conditions are known to predispose to different forms of childhood cancer including ALL. The present study characterized the spectrum and clinical impact of preexisting diseases in a cohort of ALL patients from Germany, Austria and Switzerland with a focus on genetic diseases predisposing to cancer development. Read More

    Deletion of NAD(P)H:quinone oxidoreductase 1 represses Mre11-Rad50-Nbs1 complex protein expression in cisplatin-induced nephrotoxicity.
    Toxicol Lett 2016 Jan 23;243:22-30. Epub 2015 Dec 23.
    Department of Veterinary Medicine & Institute of Veterinary Science, Chungnam National University, Daejeon 305-764, Republic of Korea. Electronic address:
    Unlabelled: The Mre11, Rad50, and Nbs1 (MRN) complex is a DNA double-strand break sensor involved in DNA damage repair. Herein, we explored whether deletion of

    Nad(p)h: quinone oxidoreductase 1 (NQO1), a cytoprotective gene, affected MRN complex expression in the kidney after cisplatin-induced acute kidney injury (AKI). In vitro, cisplatin increased the expression of MRN complex proteins and NQO1 in NQO1-expressing ACHN cells in a time- and concentration-dependent manner. Read More

    β-Lapachone enhances Mre11-Rad50-Nbs1 complex expression in cisplatin-induced nephrotoxicity.
    Pharmacol Rep 2016 Feb 28;68(1):27-31. Epub 2015 Jun 28.
    Department of Veterinary Medicine & Institute of Veterinary Science, Chungnam National University, Daejeon, Republic of Korea. Electronic address:
    Background: Recent studies suggest a potential involvement of the Mre11-Rad50-Nbs1 (MRN) complex, a DNA double-strand breaks (DSBs) sensor, in the development of nephrotoxicity following cisplatin administration. β-Lapachone is a topoisomerase I inhibitor known to reduce cisplatin-induced nephrotoxicity. In this study, by assessing MRN complex expression, we explored whether β-lapachone was involved in DNA damage response in the context of cisplatin-induced nephrotoxicity. Read More

    DNA Repair Cofactors ATMIN and NBS1 Are Required to Suppress T Cell Activation.
    PLoS Genet 2015 Nov 6;11(11):e1005645. Epub 2015 Nov 6.
    CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
    Proper development of the immune system is an intricate process dependent on many factors, including an intact DNA damage response. The DNA double-strand break signaling kinase ATM and its cofactor NBS1 are required during T cell development and for the maintenance of genomic stability. The role of a second ATM cofactor, ATMIN (also known as ASCIZ) in T cells is much less clear, and whether ATMIN and NBS1 function in synergy in T cells is unknown. Read More

    Defining ATM-Independent Functions of the Mre11 Complex with a Novel Mouse Model.
    Mol Cancer Res 2016 Feb 4;14(2):185-95. Epub 2015 Nov 4.
    Molecular Biology Program, Sloan-Kettering Institute, New York, New York.
    Unlabelled: The Mre11 complex (Mre11, Rad50, and Nbs1) occupies a central node of the DNA damage response (DDR) network and is required for ATM activation in response to DNA damage. Hypomorphic alleles of MRE11 and NBS1 confer embryonic lethality in ATM-deficient mice, indicating that the complex exerts ATM-independent functions that are essential when ATM is absent. To delineate those functions, a conditional ATM allele (ATM(flox)) was crossed to hypomorphic NBS1 mutants (Nbs1(ΔB/ΔB) mice). Read More

    OGT mediated histone H2B S112 GlcNAcylation regulates DNA damage response.
    J Genet Genomics 2015 Sep 23;42(9):467-75. Epub 2015 Jul 23.
    Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, Tianjin Industrial Microbiology Key Lab, College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, China; State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 100850, China. Electronic address:
    O-GlcNAcylation is an important post-translational modification and has been implicated in many fundamental cellular processes. Recent studies showed that O-linked N-acetylglucosamine (GlcNAc) transferase (OGT) mediated O-GlcNAcylation of histone H2B Ser 112 (H2B S112 GlcNAcylation) plays an important role in gene transcription. However, the role of this histone modification in DNA damage response has not been studied yet. Read More

    NBS1 is required for macrophage homeostasis and functional activity in mice.
    Blood 2015 Nov 31;126(22):2502-10. Epub 2015 Aug 31.
    Biology of Macrophage, Department of Physiology and Immunology, Universitat de Barcelona, Barcelona, Spain; and.
    Nijmegen breakage syndrome 1 (NBS1) is a component of the MRE11 complex, which is a sensor of DNA double-strand breaks and plays a crucial role in the DNA damage response. Because activated macrophages produce large amounts of reactive oxygen species (ROS) that can cause DNA lesions, we examined the role of NBS1 in macrophage functional activity. Proliferative and proinflammatory (interferon gamma [IFN-γ] and lipopolysaccharide [LPS]) stimuli led to increased NBS1 levels in macrophages. Read More

    Functional Role of NBS1 in Radiation Damage Response and Translesion DNA Synthesis.
    Biomolecules 2015 Aug 20;5(3):1990-2002. Epub 2015 Aug 20.
    Genome Repair Dynamics, Radiation Biology Center, Kyoto University, Yoshida Konoe, Sakyo-ku, Kyoto 606-8501, Japan.
    Nijmegen breakage syndrome (NBS) is a recessive genetic disorder characterized by increased sensitivity to ionizing radiation (IR) and a high frequency of malignancies. NBS1, a product of the mutated gene in NBS, contains several protein interaction domains in the N-terminus and C-terminus. The C-terminus of NBS1 is essential for interactions with MRE11, a homologous recombination repair nuclease, and ATM, a key player in signal transduction after the generation of DNA double-strand breaks (DSBs), which is induced by IR. Read More

    Nijmegen Breakage Syndrome: Clinical and Immunological Features, Long-Term Outcome and Treatment Options - a Retrospective Analysis.
    J Clin Immunol 2015 Aug 14;35(6):538-49. Epub 2015 Aug 14.
    Department of Immunology, Children's Memorial Health Institute, 04-730 Av. Dzieci Polskich 20, Warsaw, Poland.
    Purpose: Nijmegen Breakage Syndrome (NBS) is a rare inherited condition, characterized by microcephaly, chromosomal instability, immunodeficiency, and predisposition to malignancy. This retrospective study, characterizing the clinical and immunological status of patients with NBS at time of diagnosis, was designed to assess whether any parameters were useful in disease prognosis, and could help determine patients qualified for hematopoietic stem cell transplantation.

    Methods: The clinical and immunological characteristics of 149 NBS patients registered in the online database of the European Society for Immune Deficiencies were analyzed. Read More

    Directed Alternative Splicing in Nijmegen Breakage Syndrome: Proof of Principle Concerning Its Therapeutical Application.
    Mol Ther 2016 Feb 12;24(1):117-24. Epub 2015 Aug 12.
    Institute of Medical and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany.
    Over 90% of patients with Nijmegen breakage syndrome (NBS), a hereditary cancer disorder, are homoallelic for a 5 bp deletion in the NBN gene involved in the cellular response to DNA damage. This hypomorphic mutation leads to a carboxy-terminal protein fragment, p70-nibrin, with some residual function. Average age at malignancy, typically lymphoma, is 9. Read More

    Nbs1 ChIP-Seq Identifies Off-Target DNA Double-Strand Breaks Induced by AID in Activated Splenic B Cells.
    PLoS Genet 2015 Aug 11;11(8):e1005438. Epub 2015 Aug 11.
    Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
    Activation-induced cytidine deaminase (AID) is required for initiation of Ig class switch recombination (CSR) and somatic hypermutation (SHM) of antibody genes during immune responses. AID has also been shown to induce chromosomal translocations, mutations, and DNA double-strand breaks (DSBs) involving non-Ig genes in activated B cells. To determine what makes a DNA site a target for AID-induced DSBs, we identify off-target DSBs induced by AID by performing chromatin immunoprecipitation (ChIP) for Nbs1, a protein that binds DSBs, followed by deep sequencing (ChIP-Seq). Read More

    MCM8-9 complex promotes resection of double-strand break ends by MRE11-RAD50-NBS1 complex.
    Nat Commun 2015 Jul 28;6:7744. Epub 2015 Jul 28.
    Department of Biochemistry and Molecular Genetics, School of Medicine, University of Virginia, Jordan Hall, 1300 Jefferson Park Avenue, Charlottesville, Virginia 22908 USA.
    MCM8-9 complex is required for homologous recombination (HR)-mediated repair of double-strand breaks (DSBs). Here we report that MCM8-9 is required for DNA resection by MRN (MRE11-RAD50-NBS1) at DSBs to generate ssDNA. MCM8-9 interacts with MRN and is required for the nuclease activity and stable association of MRN with DSBs. Read More

    EXO1 is critical for embryogenesis and the DNA damage response in mice with a hypomorphic Nbs1 allele.
    Nucleic Acids Res 2015 Sep 8;43(15):7371-87. Epub 2015 Jul 8.
    Institute for Research in Biomedicine (IRB Barcelona), Barcelona 08028, Spain
    The maintenance of genome stability is critical for the suppression of diverse human pathologies that include developmental disorders, premature aging, infertility and predisposition to cancer. The DNA damage response (DDR) orchestrates the appropriate cellular responses following the detection of lesions to prevent genomic instability. The MRE11 complex is a sensor of DNA double strand breaks (DSBs) and plays key roles in multiple aspects of the DDR, including DNA end resection that is critical for signaling and DNA repair. Read More

    Nijmegen breakage syndrome protein 1 (NBS1) modulates hypoxia inducible factor-1α (HIF-1α) stability and promotes in vitro migration and invasion under ionizing radiation.
    Int J Biochem Cell Biol 2015 Jul 7;64:229-38. Epub 2015 May 7.
    Institute of Biochemistry & Molecular Biology, National Yang-Ming University, Taipei 112, Taiwan; Research Center for Tumor Medical Science, Graduate Institute of Cancer Biology, China Medical University, Taichung 404, Taiwan. Electronic address:
    Hypoxia-inducible factor (HIF) is a heterodimer transcription factor complex that monitors the cellular response to the oxygen levels in cells. Hypoxia-inducible factor-1α (HIF-1α) has been shown to be stabilized by ionizing radiation (IR) and its stabilization promotes tumor progression and metastasis. Nijmegen breakage syndrome protein 1 (NBS1), a component of the MRE11-RAD50-NBS1 complex, plays an important role in the cellular response to DNA damage but its overexpression contributes to transformation and has been found to correlate with metastasis. Read More

    Repair versus Checkpoint Functions of BRCA1 Are Differentially Regulated by Site of Chromatin Binding.
    Cancer Res 2015 Jul 4;75(13):2699-707. Epub 2015 May 4.
    Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina.
    The product of the Brca1 tumor-suppressor gene is involved in multiple aspects of the cellular DNA damage response (DDR), including activation of cell-cycle arrests and DNA double-stranded break (DSB) repair by homologous recombination. Prior reports demonstrated that BRCA1 recruitment to areas of DNA breakage depended on RAP80 and the RNF8/RNF168 E3 ubiquitin ligases. Here, we extend these findings by showing that RAP80 is only required for the binding of BRCA1 to regions flanking the DSB, whereas BRCA1 binding directly to DNA breaks requires Nijmegen breakage syndrome 1 (NBS1). Read More

    Hepatitis B virus pre-S2 mutant large surface protein inhibits DNA double-strand break repair and leads to genome instability in hepatocarcinogenesis.
    J Pathol 2015 Jul 22;236(3):337-47. Epub 2015 Apr 22.
    Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
    Although hepatitis B virus (HBV) has been established to cause hepatocellular carcinoma (HCC), the exact mechanism remains to be clarified. Type II ground glass hepatocytes (GGHs) harbouring the HBV pre-S2 mutant large surface protein (LHBS) have been recognized as a morphologically distinct hallmark of HCC in the advanced stages of chronic HBV infection. Considering its preneoplastic nature, we hypothesized that type II GGH may exhibit high genomic instability, which is important for the carcinogenic process in chronic HBV carriers. Read More

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