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.

Download full-text


Available from: Emer Bourke, May 07, 2015
  • Source
    • "More primitive, long-term repopulating stem cells are thought to be more difficult to correct than more differentiated cells[15]probably largely due to the fact that HSCs are extremely difficult to transfect or electroporate. In addition, a number of groups have identified that certain DNA repair pathways, such as HR-mediated repair, may be differentially regulated in HSCs compared to their more mature progeny[38,39]. Such defects in DNA repair may also negatively impact on the efficiency of genome editing in HSCs. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Haematopoietic stem cell transplantation is used clinically to treat many haematological conditions. Isolation of a patient’s own stem cells is a feasible approach for gene therapy and autologous transplantation, which removes the requirement for an immunologically matched donor and the restriction this causes. Manipulating the genome of blood progenitor cells is possible and represents a promising approach to correct genetic and acquired disorders using the patient’s own material. However, the efficiency and safety of gene correction in these stem cells is not yet at the level required for translation into large-scale clinical application. Current approaches, challenges and possible solutions will be discussed.
    Preview · Article · Jan 2016
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Adult stem cells and tumor-initiating cells (TICs) often employ different mechanisms of DNA damage response (DDR) as compared to other tissue cell types. However, little is known about how mammary stem cells (MaSCs) and mammary TICs respond to DNA damage. Using the mouse mammary gland and syngeneic p53-null tumors as models, we investigated the molecular and physiological consequences of DNA damage in wild-type MaSCs, p53-null MaSCs, and p53-null TICs. We showed that wild-type MaSCs and basal cells are more resistant to apoptosis and exhibit increased non-homologous end joining (NHEJ) activity. Loss of p53 in mammary epithelium affected both cell-cycle regulation and DNA repair efficiency. In p53-null tumors, we showed that TICs are more resistant to ionizing radiation (IR) due to decreased apoptosis, elevated NHEJ activity, and more-rapid DNA repair. These results have important implications for understanding DDR mechanisms involved in both tumorigenesis and therapy resistance. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Aug 2015 · Stem Cell Reports
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The mammalian organism is comprised of tissue types with varying degrees of self-renewal and regenerative capacity. In most organs self-renewing tissue-specific stem and progenitor cells contribute to organ maintenance, and it is vital to maintain a functional stem cell pool to preserve organ homeostasis. Various conditions like tissue injury, stress responses, and regeneration challenge the stem cell pool to re-establish homeostasis (Figure 1). However, with increasing age the functionality of adult stem cells declines and genomic mutations accumulate. These defects affect different cellular response pathways and lead to impairments in regeneration, stress tolerance, and organ function as well as to an increased risk for the development of ageing associated diseases and cancer. Maintenance of the genome appears to be of utmost importance to preserve stem cell function and to reduce the risk of ageing associated dysfunctions and pathologies. In this review, we discuss the causal link between stem cell dysfunction and DNA damage accrual, different strategies how stem cells maintain genome integrity, and how these processes are affected during ageing.
    Full-text · Article · Feb 2015 · Ageing Research Reviews
Show more