Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The ATM–BID pathway regulates quiescence and survival of haematopoietic stem cells

Nature Cell Biology volume 14, pages 535–541 (2012)Cite this article

Subjects

Abstract

BID, a BH3-only BCL2 family member, functions in apoptosis as well as the DNA-damage response1. Our previous data demonstrated that BID is an ATM effector acting to induce cell-cycle arrest and inhibition of apoptosis following DNA damage2,3. Here we show that ATM-mediated BID phosphorylation plays an unexpected role in maintaining the quiescence of haematopoietic stem cells (HSCs). Loss of BID phosphorylation leads to escape from quiescence of HSCs, resulting in exhaustion of the HSC pool and a marked reduction of HSC repopulating potential in vivo. We also demonstrate that BID phosphorylation plays a role in protecting HSCs from irradiation, and that regulating both quiescence and survival of HSCs depends on BID’s ability to regulate oxidative stress. Moreover, loss of BID phosphorylation, ATM knockout or exposing mice to irradiation leads to an increase in mitochondrial BID, which correlates with an increase in mitochondrial oxidative stress. These results show that the ATM–BID pathway serves as a critical checkpoint for coupling HSC homeostasis and the DNA-damage stress response to enable long-term regenerative capacity.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: BIDAA mice and haematopoietic stem and progenitor cells are hypersensitive to TBI.
Figure 2: BIDAA HSCs are less quiescent and demonstrate a competitive disadvantage in bone-marrow repopulation.
Figure 3: The quiescence capacity of HSCs depends on the ability of phosphorylated BID to regulate oxidative stress.
Figure 4: Protecting HSCs from irradiation depends on the ability of phosphorylated BID to regulate oxidative stress.
Figure 5: Loss of BID phosphorylation, ATM knockout or exposing mice to irradiation leads to an increase in both mitoBID and mitoROS.

References

  1. Yin, X. M. et al. Bid-deficient mice are resistant to Fas-induced hepatocellular apoptosis. Nature 400, 886–891 (1999).

    Article  CAS  Google Scholar 

  2. Kamer, I. et al. Proapoptotic BID is an ATM effector in the DNA-damage response. Cell 122, 593–603 (2005).

    Article  CAS  Google Scholar 

  3. Zinkel, S. S. et al. A role for proapoptotic BID in the DNA-damage response. Cell 122, 579–591 (2005).

    Article  CAS  Google Scholar 

  4. Shiloh, Y. ATM and related protein kinases: safeguarding genome integrity. Nat. Rev. Cancer 3, 155–168 (2003).

    Article  CAS  Google Scholar 

  5. Lavin, M. F. Ataxia-telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer. Nat. Rev. Mol. Cell Biol. 9, 759–769 (2008).

    Article  CAS  Google Scholar 

  6. Bartek, J., Lukas, C. & Lukas, J. Checking on DNA damage in S phase. Nat. Rev. Mol. Cell Biol. 5, 792–804 (2004).

    Article  CAS  Google Scholar 

  7. Ito, K. et al. Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature 431, 997–1002 (2004).

    Article  CAS  Google Scholar 

  8. Ito, K. et al. Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nat. Med. 12, 446–451 (2006).

    Article  CAS  Google Scholar 

  9. Whetton, A. D. Stem cells bank on ATM machine. Nat. Med. 10, 1166–1168 (2004).

    Article  CAS  Google Scholar 

  10. Barlow, C. et al. Atm-deficient mice: a paradigm of ataxia telangiectasia. Cell 86, 159–171 (1996).

    Article  CAS  Google Scholar 

  11. Celeste, A. et al. Genomic instability in mice lacking histone H2AX. Science 296, 922–927 (2002).

    Article  CAS  Google Scholar 

  12. Ward, I. M., Minn, K., van Deursen, J. & Chen, J. p53 binding protein 53BP1 is required for DNA damage responses and tumor suppression in mice. Mol. Cell Biol. 23, 2556–2563 (2003).

    Article  CAS  Google Scholar 

  13. Orford, K. W. & Scadden, D. T. Deconstructing stem cell self-renewal: genetic insights into cell-cycle regulation. Nat. Rev. Genet 9, 115–128 (2008).

    Article  CAS  Google Scholar 

  14. Liu, J. et al. Bmi1 regulates mitochondrial function and the DNA damage response pathway. Nature 459, 387–392 (2009).

    Article  CAS  Google Scholar 

  15. Molofsky, A. V. et al. Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature 425, 962–967 (2003).

    Article  CAS  Google Scholar 

  16. Park, I. K. et al. Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 423, 302–305 (2003).

    Article  CAS  Google Scholar 

  17. Mukhopadhyay, P. et al. Simultaneous detection of apoptosis and mitochondrial superoxide production in live cells by flow cytometry and confocal microscopy. Nat. Protoc. 2, 2295–2301 (2007).

    Article  CAS  Google Scholar 

  18. Cheng, T. et al. Hematopoietic stem cell quiescence maintained by p21cip1/waf1. Science 287, 1804–1808 (2000).

    Article  CAS  Google Scholar 

  19. Gan, B. et al. Lkb1 regulates quiescence and metabolic homeostasis of haematopoietic stem cells. Nature 468, 701–704 (2010).

    Article  CAS  Google Scholar 

  20. Gurumurthy, S. et al. The Lkb1 metabolic sensor maintains haematopoietic stem cell survival. Nature 468, 659–663 (2010).

    Article  CAS  Google Scholar 

  21. Hock, H. et al. Gfi-1 restricts proliferation and preserves functional integrity of haematopoietic stem cells. Nature 431, 1002–1007 (2004).

    Article  CAS  Google Scholar 

  22. Nakada, D., Saunders, T. L. & Morrison, S. J. Lkb1 regulates cell cycle and energy metabolism in haematopoietic stem cells. Nature 468, 653–658 (2010).

    Article  CAS  Google Scholar 

  23. Tothova, Z. et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 128, 325–339 (2007).

    Article  CAS  Google Scholar 

  24. Yilmaz, O. H. et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 441, 475–482 (2006).

    Article  CAS  Google Scholar 

  25. Zhang, J. et al. PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention. Nature 441, 518–522 (2006).

    Article  CAS  Google Scholar 

  26. Jang, Y. Y. & Sharkis, S. J. A low level of reactive oxygen species selects for primitive hematopoietic stem cells that may reside in the low-oxygenic niche. Blood 110, 3056–3063 (2007).

    Article  CAS  Google Scholar 

  27. Parmar, K., Mauch, P., Vergilio, J. A., Sackstein, R. & Down, J. D. Distribution of hematopoietic stem cells in the bone marrow according to regional hypoxia. Proc. Natl Acad. Sci. USA 104, 5431–5436 (2007).

    Article  CAS  Google Scholar 

  28. Tesio, M. et al. Enhanced c-Met activity promotes G-CSF-induced mobilization of hematopoietic progenitor cells via ROS signaling. Blood 117, 419–428 (2011).

    Article  CAS  Google Scholar 

  29. Juntilla, M. M. et al. AKT1 and AKT2 maintain hematopoietic stem cell function by regulating reactive oxygen species. Blood 115, 4030–4038 (2010).

    Article  CAS  Google Scholar 

  30. Zaltsman, Y. et al. MTCH2/MIMP is a major facilitator of tBID recruitment to mitochondria. Nat. Cell Biol. 12, 553–562 (2010).

    Article  CAS  Google Scholar 

  31. Willer, C. J. et al. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat. Genet 41, 25–34 (2009).

    Article  CAS  Google Scholar 

  32. Guo, Z., Kozlov, S., Lavin, M. F., Person, M. D. & Paull, T. T. ATM activation by oxidative stress. Science 330, 517–521 (2010).

    Article  CAS  Google Scholar 

  33. Andersen, J. S. et al. Directed proteomic analysis of the human nucleolus. Curr. Biol. 12, 1–11 (2002).

    Article  Google Scholar 

  34. Mihara, M. & Moll, U. M. Detection of mitochondrial localization of p53. Methods Mol. Biol. 234, 203–209 (2003).

    CAS  PubMed  Google Scholar 

  35. Grinberg, M. et al. Mitochondrial carrier homolog 2 is a target of tBID in cells signaled to die by tumor necrosis factor alpha. Mol. Cell Biol. 25, 4579–4590 (2005).

    Article  CAS  Google Scholar 

  36. George, T. C. et al. Quantitative measurement of nuclear translocation events using similarity analysis of multispectral cellular images obtained in flow. J. Immunol. Methods 311, 117–129 (2006).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to A. Harmelin, R. Haffner, A. Maizenberg, G. Damari, Y. Chermesh, C. Raanan and N. Nevo for help with the animal studies, and I. Ino, O. Amram and E. Gamil for animal maintenance. We are especially grateful to Y. Shilo (Tel Aviv University) for ATM−/− mice, and to T. Lapidot (Weizmann Institute) for advice and for reading the manuscript. We also thank A. Sharp, E. Ariel and Z. Porat for assistance with flow-cytometric studies and cell sorting and J. Lotem for advice regarding some of the studies. This study was supported in part by the Israel Science Foundation, USA–Israel Binational Science Foundation, German–Israel Foundation, German–Israel Research Program in Cancer Research, Israel Cancer Association, Minerva Stiftung and MDM ICR Research Award. A.G. is the incumbent of the Armour Family Career Development Chair of Cancer Research.

Author information

Authors and Affiliations

  1. Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel

    Maria Maryanovich, Galia Oberkovitz, Hagit Niv, Lidiya Vorobiyov, Yehudit Zaltsman & Atan Gross

  2. Department of Veterinary Resources, The Weizmann Institute of Science, Rehovot 76100, Israel

    Ori Brenner

  3. Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel

    Tsvee Lapidot & Steffen Jung

Authors
  1. Maria Maryanovich
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Galia Oberkovitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hagit Niv
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lidiya Vorobiyov
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yehudit Zaltsman
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ori Brenner
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tsvee Lapidot
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Steffen Jung
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Atan Gross
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M.M. carried out most of the experiments presented in the paper. G.O. carried out some of the initial experiments. H.N. generated the BIDAA mice and carried out the initial characterization of these mice. L.V. carried out the BID−/− and γH2AX studies, and Y.Z. helped with many of the experiments and especially with the subcellular fractionation studies. O.B. carried out the pathology of bone-marrow sections, T.L. was our consultant on HSC biology and S.J. was our main consultant on all the immunology-related studies. M.M. and A.G. planned the projects and wrote the paper. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Atan Gross.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Information (PDF 1370 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Maryanovich, M., Oberkovitz, G., Niv, H. et al. The ATM–BID pathway regulates quiescence and survival of haematopoietic stem cells. Nat Cell Biol 14, 535–541 (2012). https://doi.org/10.1038/ncb2468

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb2468

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing