title: Chromosomal Instability and Molecular Defects in Induced Pluripotent Stem Cells from Nijmegen Breakage Syndrome Patients.
abstract: 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). Our data suggest a strong selection for karyotypically normal fibroblasts to go through the reprogramming process. NBS-iPSCs then acquire numerous chromosomal aberrations and show a delayed response to DSB induction. Furthermore, NBS-iPSCs display slower growth, mitotic inhibition, a reduced apoptotic response to stress, and abnormal cell-cycle-related gene expression. Importantly, NBS neural progenitor cells (NBS-NPCs) show downregulation of neural developmental genes, which seems to be mediated by P53. Our results demonstrate the importance of NBS1 in early human development, shed light on the molecular mechanisms underlying this severe syndrome, and further expand our knowledge of the genomic stress cells experience during the reprogramming process.
authors.affiliation: The Azrieli Center for Stem Cells and Genetic Research, The Hebrew University, Givat-Ram, Jerusalem 91904, Israel; Department of Genetics, Institute of Life Sciences, The Hebrew University, Givat-Ram, Jerusalem 91904, Israel.
authors.forename: Tomer
authors.initials: T
authors.lastname: Halevy
authors.affiliation: The Azrieli Center for Stem Cells and Genetic Research, The Hebrew University, Givat-Ram, Jerusalem 91904, Israel; Department of Genetics, Institute of Life Sciences, The Hebrew University, Givat-Ram, Jerusalem 91904, Israel.
authors.forename: Shira
authors.initials: S
authors.lastname: Akov
authors.affiliation: Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich-Heine-University Duesseldorf, Moorenstrasse 5, 40225 Duesseldorf, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Bohndorf
authors.affiliation: Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich-Heine-University Duesseldorf, Moorenstrasse 5, 40225 Duesseldorf, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Mlody
authors.affiliation: Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich-Heine-University Duesseldorf, Moorenstrasse 5, 40225 Duesseldorf, Germany.
authors.forename: James
authors.initials: J
authors.lastname: Adjaye
authors.affiliation: The Azrieli Center for Stem Cells and Genetic Research, The Hebrew University, Givat-Ram, Jerusalem 91904, Israel; Department of Genetics, Institute of Life Sciences, The Hebrew University, Givat-Ram, Jerusalem 91904, Israel. Electronic address: nissimb@mail.huji.ac.il.
authors.forename: Nissim
authors.initials: N
authors.lastname: Benvenisty
authors.affiliation: Department of Genetics, Institute of Life Sciences, The Hebrew University, Givat-Ram, Jerusalem 91904, Israel. Electronic address: goldbergm@mail.huji.ac.il.
authors.forename: Michal
authors.initials: M
authors.lastname: Goldberg
mesh_terms: D017766:Acid Anhydride Hydrolases; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation; D065150:Cellular Reprogramming; D043171:Chromosomal Instability; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism* / Q000473:pathology; D007621:Karyotyping; D000076228:MRE11 Homologue Protein; D008938:Mitosis; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D058953:Neural Stem Cells / Q000378:metabolism* / Q000473:pathology; D049932:Nijmegen Breakage Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D061251:Primary Cell Culture; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; C112156:NBN protein, human; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D000076228:MRE11 Homologue Protein; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D045643:DNA Repair Enzymes