title: Quiescent hematopoietic stem cells accumulate DNA damage during aging that is repaired upon entry into cell cycle.
abstract: Hematopoietic stem cells (HSCs) maintain homeostasis and regenerate the blood system throughout life. It has been postulated that HSCs may be uniquely capable of preserving their genomic integrity in order to ensure lifelong function. To directly test this, we quantified DNA damage in HSCs and downstream progenitors from young and old mice, revealing that strand breaks significantly accrue in HSCs during aging. DNA damage accumulation in HSCs was associated with broad attenuation of DNA repair and response pathways that was dependent upon HSC quiescence. Accordingly, cycling fetal HSCs and adult HSCs driven into cycle upregulated these pathways leading to repair of strand breaks. Our results demonstrate that HSCs are not comprehensively geno-protected during aging. Rather, HSC quiescence and concomitant attenuation of DNA repair and response pathways underlies DNA damage accumulation in HSCs during aging. These results provide a potential mechanism through which premalignant mutations accrue in HSCs.
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.|Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.|Program in Cellular and Molecular Medicine, Division of Hematology/Oncology, Boston Children's Hospital, MA 02116, USA.
authors.forename: Isabel
authors.initials: I
authors.lastname: Beerman
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford CA 94305, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Seita
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford CA 94305, USA.|Sue and Bill Gross Stem Cell Research Center, Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA 92697, USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Inlay
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford CA 94305, USA.
authors.forename: Irving L
authors.initials: IL
authors.lastname: Weissman
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.|Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.|Program in Cellular and Molecular Medicine, Division of Hematology/Oncology, Boston Children's Hospital, MA 02116, USA.|Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
authors.forename: Derrick J
authors.initials: DJ
authors.lastname: Rossi
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D001854:Bone Marrow Cells / Q000502:physiology*; D063646:Carcinogenesis / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000235:genetics; D002478:Cells, Cultured; D004249:DNA Damage; D004260:DNA Repair; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006706:Homeostasis; D051379:Mice; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis; D009154:Mutation / Q000235:genetics; D018183:Transplantation Chimera