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Bcl-2 and accelerated DNA repair mediates resistance of hair follicle bulge stem cells to DNA-damage-induced cell death

Nature Cell Biology volume 12, pages 572–582 (2010)Cite this article

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Abstract

Adult stem cells (SCs) are at high risk of accumulating deleterious mutations because they reside and self-renew in adult tissues for extended periods. Little is known about how adult SCs sense and respond to DNA damage within their natural niche. Here, using mouse epidermis as a model, we define the functional consequences and the molecular mechanisms by which adult SCs respond to DNA damage. We show that multipotent hair-follicle-bulge SCs have two important mechanisms for increasing their resistance to DNA-damage-induced cell death: higher expression of the anti-apoptotic gene Bcl-2 and transient stabilization of p53 after DNA damage in bulge SCs. The attenuated p53 activation is the consequence of a faster DNA repair activity, mediated by a higher non-homologous end joining (NHEJ) activity, induced by the key protein DNA-PK. Because NHEJ is an error-prone mechanism, this novel characteristic of adult SCs may have important implications in cancer development and ageing.

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Figure 1: Bulge SCs are resistant to DNA-damage-induced cell death.
Figure 2: Resistance of bulge SCs to DNA-damage-induced cell death is not the result of their relative quiescence or the induction of senescence.
Figure 3: Bulge SCs retain their stemness and do not differentiate after DNA damage.
Figure 4: Bulge SCs undergo DNA damage after IR and activate the DDR pathway.
Figure 5: Higher Bcl-2 expression protects bulge SCs from DNA-damage-induced apoptosis.
Figure 6: Transient p53 expression protects bulge SCs from DNA-damage-induced apoptosis.
Figure 7: Bulge SCs show accelerated DNA damage repair.
Figure 8: Higher DNA-PK activity in bulge SCs leads to more efficient NHEJ activity and protects bulge SCs from DNA-damage-induced apoptosis.

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References

  1. Rossi, D. J., Jamieson, C. H. & Weissman, I. L. Stems cells and the pathways to aging and cancer. Cell 132, 681–696 (2008).

    Article  CAS  PubMed  Google Scholar 

  2. Garinis, G. A., van der Horst, G. T., Vijg, J. & Hoeijmakers, J. H. DNA damage and ageing: new-age ideas for an age-old problem. Nature Cell Biol. 10, 1241–1247 (2008).

    Article  CAS  PubMed  Google Scholar 

  3. Harper, J. W. & Elledge, S. J. The DNA damage response: ten years after. Mol. Cell 28, 739–745 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. Hoeijmakers, J. H. Genome maintenance mechanisms for preventing cancer. Nature 411, 366–374 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Harrison, J. C. & Haber, J. E. Surviving the breakup: the DNA damage checkpoint. Annu. Rev. Genet. 40, 209–235 (2006).

    Article  CAS  PubMed  Google Scholar 

  6. O'Driscoll, M. & Jeggo, P. A. The role of double-strand break repair — insights from human genetics. Nature Rev. Genet. 7, 45–54 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. Wyman, C. & Kanaar, R. DNA double-strand break repair: all's well that ends well. Annu. Rev. Genet. 40, 363–383 (2006).

    Article  CAS  PubMed  Google Scholar 

  8. d'Adda di Fagagna, F. Living on a break: cellular senescence as a DNA-damage response. Nature Rev. Cancer 8, 512–522 (2008).

    Article  CAS  Google Scholar 

  9. Riley, T., Sontag, E., Chen, P. & Levine, A. Transcriptional control of human p53-regulated genes. Nature Rev. Mol. Cell Biol. 9, 402–412 (2008).

    Article  CAS  Google Scholar 

  10. Morrison, S. J. & Spradling, A. C. Stem cells and niches: mechanisms that promote stem cell maintenance throughout life. Cell 132, 598–611 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Blanpain, C. & Fuchs, E. Epidermal homeostasis: a balancing act of stem cells in the skin. Nature Rev. Mol. Cell Biol. 10, 207–217 (2009).

    Article  CAS  Google Scholar 

  12. Trempus, C. S. et al. Enrichment for living murine keratinocytes from the hair follicle bulge with the cell surface marker CD34. J. Invest. Dermatol. 120, 501–511 (2003).

    CAS  PubMed  Google Scholar 

  13. Blanpain, C., Lowry, W. E., Geoghegan, A., Polak, L. & Fuchs, E. Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche. Cell 118, 635–648 (2004).

    Article  CAS  PubMed  Google Scholar 

  14. Tumbar, T. et al. Defining the epithelial stem cell niche in skin. Science 303, 359–363 (2004).

    Article  CAS  PubMed  Google Scholar 

  15. Morris, R. J. et al. Capturing and profiling adult hair follicle stem cells. Nature Biotechnol. 22, 411–417 (2004).

    Article  CAS  Google Scholar 

  16. Weil, M. M., Amos, C. I., Mason, K. A. & Stephens, L. C. Genetic basis of strain variation in levels of radiation-induced apoptosis of thymocytes. Radiat. Res. 146, 646–651 (1996).

    Article  CAS  PubMed  Google Scholar 

  17. Gudkov, A. V. & Komarova, E. A. The role of p53 in determining sensitivity to radiotherapy. Nature Rev. Cancer 3, 117–129 (2003).

    Article  CAS  Google Scholar 

  18. Wilson, C. et al. Cells within the bulge region of mouse hair follicle transiently proliferate during early anagen: heterogeneity and functional differences of various hair cycles. Differentiation 55, 127–136 (1994).

    Article  CAS  PubMed  Google Scholar 

  19. Inomata, K. et al. Genotoxic stress abrogates renewal of melanocyte stem cells by triggering their differentiation. Cell 137, 1088–1099 (2009).

    Article  CAS  PubMed  Google Scholar 

  20. Youssef, K. K. et al. Identification of the cell lineage at the origin of basal cell carcinoma. Nature Cell Biol. 12, 299–305 (2010).

    Article  CAS  PubMed  Google Scholar 

  21. Song, S. & Lambert, P. F. Different responses of epidermal and hair follicular cells to radiation correlate with distinct patterns of p53 and p21 induction. Am. J. Pathol. 155, 1121–1127 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Botchkarev, V. A. et al. p53 is essential for chemotherapy-induced hair loss. Cancer Res. 60, 5002–5006 (2000).

    CAS  PubMed  Google Scholar 

  23. Michalak, E., Villunger, A., Erlacher, M. & Strasser, A. Death squads enlisted by the tumour suppressor p53. Biochem. Biophys. Res. Commun. 331, 786–798 (2005).

    Article  CAS  PubMed  Google Scholar 

  24. Youle, R. J. & Strasser, A. The BCL-2 protein family: opposing activities that mediate cell death. Nature Rev. Mol. Cell Biol. 9, 47–59 (2008).

    Article  CAS  Google Scholar 

  25. Stenn, K. S., Lawrence, L., Veis, D., Korsmeyer, S. & Seiberg, M. Expression of the bcl-2 protooncogene in the cycling adult mouse hair follicle. J. Invest. Dermatol. 103, 107–111 (1994).

    Article  CAS  PubMed  Google Scholar 

  26. Michaelidis, T. M. et al. Inactivation of bcl-2 results in progressive degeneration of motoneurons, sympathetic and sensory neurons during early postnatal development. Neuron 17, 75–89 (1996).

    Article  CAS  PubMed  Google Scholar 

  27. Mendrysa, S. M. et al. mdm2 is critical for inhibition of p53 during lymphopoiesis and the response to ionizing irradiation. Mol. Cell. Biol. 23, 462–472 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Harris, S. L. & Levine, A. J. The p53 pathway: positive and negative feedback loops. Oncogene 24, 2899–2908 (2005).

    Article  CAS  PubMed  Google Scholar 

  29. Siliciano, J. D. et al. DNA damage induces phosphorylation of the amino terminus of p53. Genes Dev. 11, 3471–3481 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Bonner, W. M. et al. γH2AX and cancer. Nature Rev. Cancer 8, 957–967 (2008).

    Article  CAS  Google Scholar 

  31. Schultz, L. B., Chehab, N. H., Malikzay, A. & Halazonetis, T. D. p53 binding protein 1 (53BP1) is an early participant in the cellular response to DNA double-strand breaks. J. Cell Biol. 151, 1381–1390 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hakem, R. DNA-damage repair; the good, the bad, and the ugly. EMBO J. 27, 589–605 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Araki, R. et al. Nonsense mutation at Tyr-4046 in the DNA-dependent protein kinase catalytic subunit of severe combined immune deficiency mice. Proc. Natl Acad. Sci. USA 94, 2438–2443 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Woo, R. A., McLure, K. G., Lees-Miller, S. P., Rancourt, D. E. & Lee, P. W. DNA-dependent protein kinase acts upstream of p53 in response to DNA damage. Nature 394, 700–704 (1998).

    Article  CAS  PubMed  Google Scholar 

  35. Biedermann, K. A., Sun, J. R., Giaccia, A. J., Tosto, L. M. & Brown, J. M. scid mutation in mice confers hypersensitivity to ionizing radiation and a deficiency in DNA double-strand break repair. Proc. Natl Acad. Sci. USA 88, 1394–1397 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Fulop, G. M. & Phillips, R. A. The scid mutation in mice causes a general defect in DNA repair. Nature 347, 479–482 (1990).

    Article  CAS  PubMed  Google Scholar 

  37. Potten, C. S., Wilson, J. W. & Booth, C. Regulation and significance of apoptosis in the stem cells of the gastrointestinal epithelium. Stem Cells 15, 82–93 (1997).

    Article  CAS  PubMed  Google Scholar 

  38. Barker, N. et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003–1007 (2007).

    Article  CAS  PubMed  Google Scholar 

  39. Marshman, E., Booth, C. & Potten, C. S. The intestinal epithelial stem cell. BioEssays 24, 91–98 (2002).

    Article  PubMed  Google Scholar 

  40. Sangiorgi, E. & Capecchi, M. R. Bmi1 is expressed in vivo in intestinal stem cells. Nature Genet. 40, 915–920 (2008).

    Article  CAS  PubMed  Google Scholar 

  41. Wilson, J. W., Pritchard, D. M., Hickman, J. A. & Potten, C. S. Radiation-induced p53 and p21WAF-1/CIP1 expression in the murine intestinal epithelium: apoptosis and cell cycle arrest. Am. J. Pathol. 153, 899–909 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Potten, C. S., Owen, G. & Booth, D. Intestinal stem cells protect their genome by selective segregation of template DNA strands. J. Cell Sci. 115, 2381–2388 (2002).

    CAS  PubMed  Google Scholar 

  43. Fitzgerald, T. J. et al. Radiation therapy toxicity to the skin. Dermatol. Clin. 26, 161–172, ix (2008).

    Article  CAS  PubMed  Google Scholar 

  44. Stone, H. B., Coleman, C. N., Anscher, M. S. & McBride, W. H. Effects of radiation on normal tissue: consequences and mechanisms. Lancet Oncol. 4, 529–536 (2003).

    Article  CAS  PubMed  Google Scholar 

  45. Dorr, W. Skin and other reactions to radiotherapy — clinical presentation and radiobiology of skin reactions. Front. Radiat. Ther. Oncol. 39, 96–101 (2006).

    PubMed  Google Scholar 

  46. Kim, D. J. et al. Targeted disruption of Bcl-xL in mouse keratinocytes inhibits both UVB- and chemically induced skin carcinogenesis. Mol. Carcinog. 48, 873–885 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Merritt, A. J. et al. The role of p53 in spontaneous and radiation-induced apoptosis in the gastrointestinal tract of normal and p53-deficient mice. Cancer Res. 54, 614–617 (1994).

    CAS  PubMed  Google Scholar 

  48. Merritt, A. J. et al. Differential expression of bcl-2 in intestinal epithelia. Correlation with attenuation of apoptosis in colonic crypts and the incidence of colonic neoplasia. J. Cell Sci. 108, 2261–2271 (1995).

    CAS  PubMed  Google Scholar 

  49. Potten, C. S. Radiation, the ideal cytotoxic agent for studying the cell biology of tissues such as the small intestine. Radiat. Res. 161, 123–136 (2004).

    Article  CAS  PubMed  Google Scholar 

  50. Kemp, C. J., Vo, K. & Gurley, K. E. Resistance to skin tumorigenesis in DNAPK-deficient SCID mice is not due to immunodeficiency but results from hypersensitivity to TPA-induced apoptosis. Carcinogenesis 20, 2051–2056 (1999).

    Article  CAS  PubMed  Google Scholar 

  51. Ramalho-Santos, M., Yoon, S., Matsuzaki, Y., Mulligan, R. C. & Melton, D. A. 'Stemness': transcriptional profiling of embryonic and adult stem cells. Science 298, 597–600 (2002).

    Article  CAS  PubMed  Google Scholar 

  52. Ivanova, N. B. et al. A stem cell molecular signature. Science 298, 601–604 (2002).

    Article  CAS  PubMed  Google Scholar 

  53. Rossi, D. J. et al. Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature 447, 725–729 (2007).

    Article  CAS  PubMed  Google Scholar 

  54. Nijnik, A. et al. DNA repair is limiting for haematopoietic stem cells during ageing. Nature 447, 686–690 (2007).

    Article  CAS  PubMed  Google Scholar 

  55. Ploemacher, R. E., van Os, R., van Beurden, C. A. & Down, J. D. Murine haemopoietic stem cells with long-term engraftment and marrow repopulating ability are more resistant to gamma-radiation than are spleen colony forming cells. Int. J. Radiat. Biol. 61, 489–499 (1992).

    Article  CAS  PubMed  Google Scholar 

  56. Meijne, E. I. et al. The effects of x-irradiation on hematopoietic stem cell compartments in the mouse. Exp. Hematol. 19, 617–623 (1991).

    CAS  PubMed  Google Scholar 

  57. Down, J. D., Boudewijn, A., van Os, R., Thames, H. D. & Ploemacher, R. E. Variations in radiation sensitivity and repair among different hematopoietic stem cell subsets following fractionated irradiation. Blood 86, 122–127 (1995).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the members of the Blanpain and Vanderhaeghen laboratories for comments during the realization of this study. We thank V. de Maertelaer for help with the statistical analyses. C.B. is a chercheur qualifié of the Fonds de la Recherche Scientifique (F.R.S.)/Fonds National de la Recherche Scientifique (FNRS). A.C. is a research fellow of the F.R.S./Fonds pour la formation à la Recherche dans l'Industrie et dans l'Agriculture (FRIA). This work was supported by a 'mandat d'impulsion scientifique' of the FNRS, a career development award of the Human Frontier Science Program Organization (HFSPO), a research grant of the Schlumberger Foundation, the programme CIBLES of the Wallonia Region, a research grant from the Fondation Contre le Cancer and the fond Gaston Ithier, a starting grant of the European Research Council (ERC) and the EMBO Young Investigator Program.

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  1. Panagiota A. Sotiropoulou and Aurélie Candi: These authors contributed equally to this work.

Authors and Affiliations

  1. Interdisciplinary Research Institute (IRIBHM), Université Libre de Bruxelles (ULB), 808, route de Lennik, BatC, C6-130, 1070, Brussels, Belgium

    Panagiota A. Sotiropoulou, Aurélie Candi, Guilhem Mascré, Khalil Kass Youssef, Gaelle Lapouge, Ellen Dahl, Claudio Semeraro & Cédric Blanpain

  2. VIB, UGent, Laboratory for Molecular Cancer Biology, Belgium

    Sarah De Clercq, Geertrui Denecker & Jean-Christophe Marine

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Contributions

C.B., P.A.S., A.C., S.D.C., G.D. and J.C.M. designed the experiments and performed data analysis. P.A.S., A.C., K.K.Y., G.M. and G.L. performed most of the experiments. S.D.C., G.D. and JC.M. performed the western blot analysis. E.D. and C.S. provided technical support. C.B. and P.A.S. wrote the manuscript.

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Correspondence to Cédric Blanpain.

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Sotiropoulou, P., Candi, A., Mascré, G. et al. Bcl-2 and accelerated DNA repair mediates resistance of hair follicle bulge stem cells to DNA-damage-induced cell death. Nat Cell Biol 12, 572–582 (2010). https://doi.org/10.1038/ncb2059

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