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Cell Rep. 2016 Aug 30;16(9):2499-511. doi: 10.1016/j.celrep.2016.07.071. Epub 2016 Aug 18.

Chromosomal Instability and Molecular Defects in Induced Pluripotent Stem Cells from Nijmegen Breakage Syndrome Patients.

Author information

1
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.
2
Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich-Heine-University Duesseldorf, Moorenstrasse 5, 40225 Duesseldorf, Germany.
3
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.
4
Department of Genetics, Institute of Life Sciences, The Hebrew University, Givat-Ram, Jerusalem 91904, Israel. Electronic address: goldbergm@mail.huji.ac.il.

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.

PMID:
27545893
DOI:
10.1016/j.celrep.2016.07.071
[Indexed for MEDLINE]
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