Abstract
Hematopoietic stem cells (HSCs) maintain hematopoietic homeostasis throughout a mammal’s lifespan through self-renewal and differentiation into mature blood cells. Within a bone marrow niche, HSCs adopt a quiescent state and remain in the non-dividing, G0 phase of the cell cycle. It was recently shown that maintenance of genomic integrity is crucial for the preservation of self-renewal capacity of HSCs. In this review, we focus on progress in elucidating the roles of reactive oxygen species (ROS) and DNA damage responses (DDR) in maintaining genomic integrity, and thus HSC function. Several studies have demonstrated that inappropriate ROS levels arising from disruption of the Atm, PI3K-Akt, or Mdm2-p53 pathways impair HSC function in vivo. Intriguing evidence that stem cells use specific DDR mechanisms is also accumulating. Although murine HSCs are more resistant than progenitor cells to mild DNA damage in vivo, the surviving HSCs frequently acquire genetic aberrations that can lead to leukemogenesis. Indeed, non-dividing HSCs employ the error-prone non-homologous end-joining pathway of DNA repair to fix DNA breaks, whereas progenitors undergo apoptosis; proliferating HSCs employ the high-fidelity homologous recombination mechanism. Dissection of HSC-specific mechanisms for the maintenance of genomic integrity may provide valuable insights into the biology of both HSCs and leukemia stem cells.
Similar content being viewed by others
References
Arai F, Hirao A, Suda T. Regulation of hematopoiesis and its interaction with stem cell niches. Int J Hematol. 2005;82(5):371–6.
Kiel MJ, Morrison SJ. Uncertainty in the niches that maintain haematopoietic stem cells. Nat Rev Immunol. 2008;8(4):290–301.
Vaziri H, Dragowska W, Allsopp RC, Thomas TE, Harley CB, Lansdorp PM. Evidence for a mitotic clock in human hematopoietic stem cells: loss of telomeric DNA with age. Proc Natl Acad Sci USA. 1994;91(21):9857–60.
Samper E, Fernandez P, Eguia R, et al. Long-term repopulating ability of telomerase-deficient murine hematopoietic stem cells. Blood. 2002;99(8):2767–75.
Allsopp RC, Morin GB, DePinho R, Harley CB, Weissman IL. Telomerase is required to slow telomere shortening and extend replicative lifespan of HSCs during serial transplantation. Blood. 2003;102(2):517–20.
Parmar K, Kim J, Sykes SM, et al. Hematopoietic stem cell defects in mice with deficiency of Fancd2 or Usp1. Stem Cells. 2010;28(7):1186–95.
Zhang QS, Marquez-Loza L, Eaton L, et al. Fancd2 −/− mice have hematopoietic defects that can be partially corrected by resveratrol. Blood. 2010;116(24):5140–8.
Takubo K, Goda N, Yamada W, et al. Regulation of the HIF-1α level is essential for hematopoietic stem cells. Cell Stem Cell. 2010;7(3):391–402.
Jang YY, Sharkis SJ. A low level of reactive oxygen species selects for primitive hematopoietic stem cells that may reside in the low-oxygenic niche. Blood. 2007;110(8):3056–63.
Ito K, Hirao A, Arai F, et al. Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nat Med. 2006;12(4):446–51.
Ito K, Hirao A, Arai F, et al. Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature. 2004;431(7011):997–1002.
Greer EL, Brunet A. FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene. 2005;24(50):7410–25.
Yamazaki S, Iwama A, Takayanagi S, et al. Cytokine signals modulated via lipid rafts mimic niche signals and induce hibernation in hematopoietic stem cells. EMBO J. 2006;25(15):3515–23.
Tothova Z, Kollipara R, Huntly BJ, et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell. 2007;128(2):325–39.
Miyamoto K, Araki KY, Naka K, et al. Foxo3a is essential for maintenance of the hematopoietic stem cell pool. Cell Stem Cell. 2007;1(1):101–12.
Yalcin S, Zhang X, Luciano JP, et al. Foxo3 is essential for the regulation of ataxia telangiectasia mutated and oxidative stress-mediated homeostasis of hematopoietic stem cells. J Biol Chem. 2008;283(37):25692–705.
Naka K, Hoshii T, Muraguchi T, et al. TGF-β-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia. Nature. 2010;463(7281):676–80.
Gan B, Sahin E, Jiang S, et al. mTORC1-dependent and -independent regulation of stem cell renewal, differentiation, and mobilization. Proc Natl Acad Sci USA. 2008;105(49):19384–9.
Chen C, Liu Y, Liu R, Ikenoue T, Guan KL, Zheng P. TSC-mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen species. J Exp Med. 2008;205(10):2397–408.
Lee JY, Nakada D, Yilmaz OH, et al. mTOR activation induces tumor suppressors that inhibit leukemogenesis and deplete hematopoietic stem cells after Pten deletion. Cell Stem Cell. 2010;7(5):593–605.
Abbas HA, Maccio DR, Coskun S, et al. Mdm2 is required for survival of hematopoietic stem cells/progenitors via dampening of ROS-induced p53 activity. Cell Stem Cell. 2010;7(5):606–17.
Rossi DJ, Bryder D, Seita J, Nussenzweig A, Hoeijmakers J, Weissman IL. Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature. 2007;447(7145):725–9.
Nijnik A, Woodbine L, Marchetti C, et al. DNA repair is limiting for haematopoietic stem cells during ageing. Nature. 2007;447(7145):686–90.
Milyavsky M, Gan OI, Trottier M, et al. A distinctive DNA damage response in human hematopoietic stem cells reveals an apoptosis-independent role for p53 in self-renewal. Cell Stem Cell. 2010;7(2):186–97.
Mohrin M, Bourke E, Alexander D, et al. Hematopoietic stem cell quiescence promotes error-prone DNA repair and mutagenesis. Cell Stem Cell. 2010;7(2):174–85.
Branzei D, Foiani M. Regulation of DNA repair throughout the cell cycle. Nat Rev Mol Cell Biol. 2008;9(4):297–308.
Bondar T, Medzhitov R. p53-mediated hematopoietic stem and progenitor cell competition. Cell Stem Cell. 2010;6(4):309–22.
Author information
Authors and Affiliations
Corresponding author
About this article
Cite this article
Naka, K., Hirao, A. Maintenance of genomic integrity in hematopoietic stem cells. Int J Hematol 93, 434–439 (2011). https://doi.org/10.1007/s12185-011-0793-z
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12185-011-0793-z