Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2015 Apr 23;520(7548):549-52.
doi: 10.1038/nature14131. Epub 2015 Feb 18.

Exit from dormancy provokes DNA-damage-induced attrition in haematopoietic stem cells

Affiliations

Exit from dormancy provokes DNA-damage-induced attrition in haematopoietic stem cells

Dagmar Walter et al. Nature. .

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.

PubMed Disclaimer

Similar articles

Cited by

References

    1. Hematology Am Soc Hematol Educ Program. 2006;:72-7 - PubMed
    1. Blood. 2006 Sep 1;108(5):1533-41 - PubMed
    1. Cell. 2008 Feb 22;132(4):681-96 - PubMed
    1. Cell. 2008 Dec 12;135(6):1118-29 - PubMed
    1. Stem Cells Dev. 2007 Oct;16(5):707-17 - PubMed

Publication types

Substances