Chromosomal Instability and Molecular Defects in Induced Pluripotent Stem Cells from Nijmegen Breakage Syndrome Patients
Tomer Halevy,
Shira Akov,
Martina Bohndorf,
Barbara Mlody,
James Adjaye,
Nissim Benvenisty,
Michal Goldberg
Affiliations
Tomer Halevy
The Azrieli Center for Stem Cells and Genetic Research, The Hebrew University, Givat-Ram, Jerusalem 91904, Israel
Shira Akov
The Azrieli Center for Stem Cells and Genetic Research, The Hebrew University, Givat-Ram, Jerusalem 91904, Israel
Martina Bohndorf
Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich-Heine-University Duesseldorf, Moorenstrasse 5, 40225 Duesseldorf, Germany
Barbara Mlody
Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich-Heine-University Duesseldorf, Moorenstrasse 5, 40225 Duesseldorf, Germany
James Adjaye
Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich-Heine-University Duesseldorf, Moorenstrasse 5, 40225 Duesseldorf, Germany
Nissim Benvenisty
The Azrieli Center for Stem Cells and Genetic Research, The Hebrew University, Givat-Ram, Jerusalem 91904, Israel
Michal Goldberg
Department of Genetics, Institute of Life Sciences, The Hebrew University, Givat-Ram, Jerusalem 91904, Israel
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.
