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@ARTICLE{Walter:127743,
      author       = {D. Walter$^*$ and A. Lier$^*$ and A. Geiselhart$^*$ and F.
                      B. Thalheimer and S. Huntscha$^*$ and M. C. Sobotta$^*$ and
                      B. Moehrle and D. Brocks$^*$ and I. Bayindir$^*$ and P. E.
                      Kaschutnig$^*$ and K. Muedder$^*$ and C. Klein$^*$ and A.
                      Jauch and T. Schroeder and H. Geiger and T. Dick$^*$ and T.
                      Holland-Letz$^*$ and P. Schmezer$^*$ and S. W. Lane and M.
                      A. Rieger and M. Essers$^*$ and D. A. Williams and A.
                      Trumpp$^*$ and M. Milsom$^*$},
      title        = {{E}xit from dormancy provokes {DNA}-damage-induced
                      attrition in haematopoietic stem cells.},
      journal      = {Nature},
      volume       = {520},
      number       = {7548},
      issn         = {1476-4687},
      address      = {London [u.a.]},
      publisher    = {Nature Publ. Group},
      reportid     = {DKFZ-2017-03766},
      pages        = {549 - 552},
      year         = {2015},
      abstract     = {Haematopoietic stem cells (HSCs) are responsible for the
                      lifelong production of blood cells. The accumulation of DNA
                      damage in HSCs is a hallmark of ageing and is probably a
                      major contributing factor in age-related tissue degeneration
                      and malignant transformation. A number of accelerated ageing
                      syndromes are associated with defective DNA repair and
                      genomic instability, including the most common inherited
                      bone marrow failure syndrome, Fanconi anaemia. However, the
                      physiological source of DNA damage in HSCs from both normal
                      and diseased individuals remains unclear. Here we show in
                      mice that DNA damage is a direct consequence of inducing
                      HSCs to exit their homeostatic quiescent state in response
                      to conditions that model physiological stress, such as
                      infection or chronic blood loss. Repeated activation of HSCs
                      out of their dormant state provoked the attrition of normal
                      HSCs and, in the case of mice with a non-functional Fanconi
                      anaemia DNA repair pathway, led to a complete collapse of
                      the haematopoietic system, which phenocopied the highly
                      penetrant bone marrow failure seen in Fanconi anaemia
                      patients. Our findings establish a novel link between
                      physiological stress and DNA damage in normal HSCs and
                      provide a mechanistic explanation for the universal
                      accumulation of DNA damage in HSCs during ageing and the
                      accelerated failure of the haematopoietic system in Fanconi
                      anaemia patients.},
      keywords     = {Reactive Oxygen Species (NLM Chemicals)},
      cin          = {A010 / A160 / A012 / A011 / C060 / C010},
      ddc          = {070},
      cid          = {I:(DE-He78)A010-20160331 / I:(DE-He78)A160-20160331 /
                      I:(DE-He78)A012-20160331 / I:(DE-He78)A011-20160331 /
                      I:(DE-He78)C060-20160331 / I:(DE-He78)C010-20160331},
      pnm          = {311 - Signalling pathways, cell and tumor biology
                      (POF3-311)},
      pid          = {G:(DE-HGF)POF3-311},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:25707806},
      doi          = {10.1038/nature14131},
      url          = {https://inrepo02.dkfz.de/record/127743},
}