TY  - JOUR
AU  - Walter, Dagmar
AU  - Lier, Amelie
AU  - Geiselhart, Anja
AU  - Thalheimer, Frederic B
AU  - Huntscha, Sina
AU  - Sobotta, Mirko C
AU  - Moehrle, Bettina
AU  - Brocks, David
AU  - Bayindir, Irem
AU  - Kaschutnig, Paul Emanuel
AU  - Muedder, Katja
AU  - Klein, Corinna
AU  - Jauch, Anna
AU  - Schroeder, Timm
AU  - Geiger, Hartmut
AU  - Dick, Tobias
AU  - Holland-Letz, Tim
AU  - Schmezer, Peter
AU  - Lane, Steven W
AU  - Rieger, Michael A
AU  - Essers, Marieke
AU  - Williams, David A
AU  - Trumpp, Andreas
AU  - Milsom, Michael
TI  - Exit from dormancy provokes DNA-damage-induced attrition in haematopoietic stem cells.
JO  - Nature 
VL  - 520
IS  - 7548
SN  - 1476-4687
CY  - London [u.a.]
PB  - Nature Publ. Group
M1  - DKFZ-2017-03766
SP  - 549 - 552
PY  - 2015
AB  - 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.
KW  - Reactive Oxygen Species (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:25707806
DO  - DOI:10.1038/nature14131
UR  - https://inrepo02.dkfz.de/record/127743
ER  -