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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: 22.15). 08/2010; 7(2):174-85. DOI: 10.1016/j.stem.2010.06.014
Source: PubMed

ABSTRACT 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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    • "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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    • "HSC fate choices can result from the interplay of several cellintrinsic regulatory networks [33]. Thus, HSC survival is dictated in part by the balance of pro-and anti-apoptotic Bcl2 family proteins [28], while differentiation is regulated by the stochastic activation of lineage-specific transcription factor networks such as the antagonistic GATA-1/PU.1 axis driving erythroid and myeloid differentiation [23]. Other transcriptional and epigenetic factors, including Bmi-1, p53, Ikaros and C/EBPα also play key roles in directing HSC fate decisions [15] [23]. "
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