A Differentiation Checkpoint Limits Hematopoietic Stem Cell Self-Renewal in Response to DNA Damage | Zendy

Jianwei Wang | Zendy; Qian Sun | Zendy; Yohei Morita | Zendy; Hong Jiang | Zendy; Alexander Groß | Zendy; André Lechel | Zendy; Kai Hildner | Zendy; Luis Miguel Guachalla | Zendy; Anne Gompf | Zendy; Daniel Hartmann | Zendy; Axel Schambach | Zendy; Torsten Wüestefeld | Zendy; Daniel Dauch | Zendy; Hubert Schrezenmeier | Zendy; WolfKarsten Hofmann | Zendy; Hiromitsu Nakauchi | Zendy; Zhenyu Ju | Zendy; Hans A. Kestler | Zendy; Lars Zender | Zendy; K. Lenhard Rudolph | Zendy

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A Differentiation Checkpoint Limits Hematopoietic Stem Cell Self-Renewal in Response to DNA Damage

Author(s) -

Jianwei Wang,

Qian Sun,

Yohei Morita,

Hong Jiang,

Alexander Groß,

André Lechel,

Kai Hildner,

Luis Miguel Guachalla,

Anne Gompf,

Daniel Hartmann,

Axel Schambach,

Torsten Wüestefeld,

Daniel Dauch,

Hubert Schrezenmeier,

WolfKarsten Hofmann,

Hiromitsu Nakauchi,

Zhenyu Ju,

Hans A. Kestler,

Lars Zender,

K. Lenhard Rudolph

Publication year - 2012

Publication title -

cell

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 26.304

H-Index - 776

eISSN - 1097-4172

pISSN - 0092-8674

DOI - 10.1016/j.cell.2012.01.040

Subject(s) - biology , g2 m dna damage checkpoint , dna damage , haematopoiesis , stem cell , microbiology and biotechnology , hematopoietic stem cell , dna , genetics , cell cycle checkpoint , cancer research , cell , cell cycle

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.

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