Hematopoietic Stem Cell Quiescence Promotes Error-Prone DNA Repair and Mutagenesis

The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Department of Medicine, Division of Hematology/Oncology, University of California San Francisco, San Francisco, CA 94143, USA.
Cell stem cell (Impact Factor: 22.27). 08/2010; 7(2):174-85. DOI: 10.1016/j.stem.2010.06.014
Source: PubMed


Most adult stem cells, including hematopoietic stem cells (HSCs), are maintained in a quiescent or resting state in vivo. Quiescence is widely considered to be an essential protective mechanism for stem cells that minimizes endogenous stress caused by cellular respiration and DNA replication. We demonstrate that HSC quiescence can also have detrimental effects. We found that HSCs have unique cell-intrinsic mechanisms ensuring their survival in response to ionizing irradiation (IR), which include enhanced prosurvival gene expression and strong activation of p53-mediated DNA damage response. We show that quiescent and proliferating HSCs are equally radioprotected but use different types of DNA repair mechanisms. We describe how nonhomologous end joining (NHEJ)-mediated DNA repair in quiescent HSCs is associated with acquisition of genomic rearrangements, which can persist in vivo and contribute to hematopoietic abnormalities. Our results demonstrate that quiescence is a double-edged sword that renders HSCs intrinsically vulnerable to mutagenesis following DNA damage.

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Available from: Emer Bourke, May 07, 2015
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    • "These observations suggest that, once damage occurs, p53-null tumor cells have an increase probability to accumulate mutations as compared to MECs. Finally, the increased activity of the NHEJ repair pathway in MaSCs and TICs might be a doubleedged sword because NHEJ is an error-prone repair mechanism (Khanna and Jackson, 2001) and might, therefore, allow more mutations to accumulate over time (Mohrin et al., 2010). "
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    • "However, this independence of a template uncouples NHEJ from the cell cycle allowing execution of repair also during G0/G1. Since HSCs usually are quiescent and divide only rarely, they predominantly use NHEJ to repair DSBs (Mohrin et al., 2010). Although preferential use of the error-prone NHEJ allows quick repair of DSBs, this bears the risk of an elevated mutation rate. "
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    • "Limbal basal cells remain quiescent but proceed more rapidly through the cell cycle when there is an insult to the ocular surface such as a wound or tumour promoter (Cotsarelis et al., 1989). Quiescent adult stem cells accumulate DNA damage making them vulnerable to neoplastic transformation (Mohrin et al., 2010). Others however suggest that slow-cycling protects them from cancer (Wodarz, 2007). "
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