title: Stem Cell-Specific Mechanisms Ensure Genomic Fidelity within HSCs and upon Aging of HSCs.
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.
authors.affiliation: Institute of Molecular Medicine, University of Ulm, 89081 Ulm, Germany.
authors.forename: Bettina M
authors.initials: BM
authors.lastname: Moehrle
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Kalpana
authors.initials: K
authors.lastname: Nattamai
authors.affiliation: Institute of Molecular Medicine, University of Ulm, 89081 Ulm, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Brown
authors.affiliation: Institute of Molecular Medicine, University of Ulm, 89081 Ulm, Germany.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Florian
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Marnie
authors.initials: M
authors.lastname: Ryan
authors.affiliation: Institute of Molecular Medicine, University of Ulm, 89081 Ulm, Germany.
authors.forename: Mona
authors.initials: M
authors.lastname: Vogel
authors.affiliation: Institute of Molecular Medicine, University of Ulm, 89081 Ulm, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Bliederhaeuser
authors.affiliation: Institute of Molecular Medicine, University of Ulm, 89081 Ulm, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Soller
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Prows
authors.affiliation: German Cancer Consortium (DKTK), 69120 Heidelberg, Germany; Molecular and Translational Radiation Oncology, Heidelberg Ion Therapy Center (HIT), 69120 Heidelberg, Germany.
authors.forename: Amir
authors.initials: A
authors.lastname: Abdollahi
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: David
authors.initials: D
authors.lastname: Schleimer
authors.affiliation: Heidelberg Institute for Stem Cell Technology and Experimental Medicine gGmbH (HI-STEM), 69120 Heidelberg, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Walter
authors.affiliation: 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.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Milsom
authors.affiliation: Department of Molecular Genetics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Stambrook
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, CA 94305, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Porteus
authors.affiliation: 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.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Geiger
mesh_terms: D000375:Aging; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D001854:Bone Marrow Cells / Q000166:cytology; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D064447:Checkpoint Kinase 2 / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000528:radiation effects; D004706:Endodeoxyribonucleases / Q000235:genetics / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints / Q000528:radiation effects; D005720:Gamma Rays; D016678:Genome; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D019656:Loss of Heterozygosity; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D059807:S Phase Cell Cycle Checkpoints / Q000528:radiation effects; D014184:Transplantation, Homologous; D014916:Whole-Body Irradiation
chemical_list: D064447:Checkpoint Kinase 2; C578633:Chek2 protein, mouse; D004706:Endodeoxyribonucleases