title: A differentiation checkpoint limits hematopoietic stem cell self-renewal in response to DNA damage.
abstract: Checkpoints that limit stem cell self-renewal in response to DNA damage can contribute to cancer protection but may also promote tissue aging. Molecular components that control stem cell responses to DNA damage remain to be delineated. Using in vivo RNAi screens, we identified basic leucine zipper transcription factor, ATF-like (BATF) as a major component limiting self-renewal of hematopoietic stem cells (HSCs) in response to telomere dysfunction and γ-irradiation. DNA damage induces BATF in a G-CSF/STAT3-dependent manner resulting in lymphoid differentiation of HSCs. BATF deletion improves HSC self-renewal and function in response to γ-irradiation or telomere shortening but results in accumulation of DNA damage in HSCs. Analysis of bone marrow from patients with myelodysplastic syndrome supports the conclusion that DNA damage-dependent induction of BATF is conserved in human HSCs. Together, these results provide experimental evidence that a BATF-dependent differentiation checkpoint limits self-renewal of HSCs in response to DNA damage.
authors.affiliation: Institute of Molecular Medicine and Max-Planck-Research Department of Stem Cell Aging, University of Ulm, Ulm, Germany.
authors.forename: Jianwei
authors.initials: J
authors.lastname: Wang
authors.forename: Qian
authors.initials: Q
authors.lastname: Sun
authors.forename: Yohei
authors.initials: Y
authors.lastname: Morita
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
authors.forename: Alexander
authors.initials: A
authors.lastname: Gross
authors.forename: André
authors.initials: A
authors.lastname: Lechel
authors.forename: Kai
authors.initials: K
authors.lastname: Hildner
authors.forename: Luis Miguel
authors.initials: LM
authors.lastname: Guachalla
authors.forename: Anne
authors.initials: A
authors.lastname: Gompf
authors.forename: Daniel
authors.initials: D
authors.lastname: Hartmann
authors.forename: Axel
authors.initials: A
authors.lastname: Schambach
authors.forename: Torsten
authors.initials: T
authors.lastname: Wuestefeld
authors.forename: Daniel
authors.initials: D
authors.lastname: Dauch
authors.forename: Hubert
authors.initials: H
authors.lastname: Schrezenmeier
authors.forename: Wolf-Karsten
authors.initials: WK
authors.lastname: Hofmann
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Nakauchi
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Ju
authors.forename: Hans A
authors.initials: HA
authors.lastname: Kestler
authors.forename: Lars
authors.initials: L
authors.lastname: Zender
authors.forename: K Lenhard
authors.initials: KL
authors.lastname: Rudolph
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints; D002454:Cell Differentiation; D016922:Cellular Senescence; D004249:DNA Damage; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D013047:Specific Pathogen-Free Organisms; D059506:Telomere Shortening