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Cell Rep. 2015 Dec 22;13(11):2412-2424. doi: 10.1016/j.celrep.2015.11.030. Epub 2015 Dec 10.

Stem Cell-Specific Mechanisms Ensure Genomic Fidelity within HSCs and upon Aging of HSCs.

Author information

1
Institute of Molecular Medicine, University of Ulm, 89081 Ulm, Germany.
2
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, OH 45229, USA.
3
Division of Human Genetics, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, OH 45229, USA.
4
German Cancer Consortium (DKTK), 69120 Heidelberg, Germany; Molecular and Translational Radiation Oncology, Heidelberg Ion Therapy Center (HIT), 69120 Heidelberg, Germany.
5
Heidelberg Institute for Stem Cell Technology and Experimental Medicine gGmbH (HI-STEM), 69120 Heidelberg, Germany.
6
Heidelberg Institute for Stem Cell Technology and Experimental Medicine gGmbH (HI-STEM), 69120 Heidelberg, Germany; Deutsches Krebsforschungszentrum (DKFZ), Division of Stem Cells and Cancer, Experimental Hematology Group, 69120 Heidelberg, Germany.
7
Department of Molecular Genetics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
8
Department of Pediatrics, Stanford University, Stanford, CA 94305, USA.
9
Institute of Molecular Medicine, University of Ulm, 89081 Ulm, Germany; Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, OH 45229, USA. Electronic address: hartmut.geiger@uni-ulm.de.

Abstract

Whether aged hematopoietic stem and progenitor cells (HSPCs) have impaired DNA damage repair is controversial. Using a combination of DNA mutation indicator assays, we observe a 2- to 3-fold increase in the number of DNA mutations in the hematopoietic system upon aging. Young and aged hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) do not show an increase in mutation upon irradiation-induced DNA damage repair, and young and aged HSPCs respond very similarly to DNA damage with respect to cell-cycle checkpoint activation and apoptosis. Both young and aged HSPCs show impaired activation of the DNA-damage-induced G1-S checkpoint. Induction of chronic DNA double-strand breaks by zinc-finger nucleases suggests that HSPCs undergo apoptosis rather than faulty repair. These data reveal a protective mechanism in both the young and aged hematopoietic system against accumulation of mutations in response to DNA damage.

PMID:
26686632
PMCID:
PMC4691560
DOI:
10.1016/j.celrep.2015.11.030
[Indexed for MEDLINE]
Free PMC Article

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