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.

  • Letter
  • Published:

Puma and p21 represent cooperating checkpoints limiting self-renewal and chromosomal instability of somatic stem cells in response to telomere dysfunction

Nature Cell Biology volume 14, pages 73–79 (2012)Cite this article

An Author Correction to this article was published on 28 January 2021

This article has been updated

Abstract

The tumour suppressor p53 activates Puma-dependent apoptosis and p21-dependent cell-cycle arrest in response to DNA damage. Deletion of p21 improved stem-cell function and organ maintenance in progeroid mice with dysfunctional telomeres, but the function of Puma has not been investigated in this context. Here we show that deletion of Puma improves stem- and progenitor-cell function, organ maintenance and lifespan of telomere-dysfunctional mice. Puma deletion impairs the clearance of stem and progenitor cells that have accumulated DNA damage as a consequence of critically short telomeres. However, further accumulation of DNA damage in these rescued progenitor cells leads to increasing activation of p21. RNA interference experiments show that upregulation of p21 limits proliferation and evolution of chromosomal imbalances of Puma-deficient stem and progenitor cells with dysfunctional telomeres. These results provide experimental evidence that p53-dependent apoptosis and cell-cycle arrest act in cooperating checkpoints limiting tissue maintenance and evolution of chromosomal instability at stem- and progenitor-cell levels in response to telomere dysfunction. Selective inhibition of Puma-dependent apoptosis can result in temporary improvements in maintenance of telomere-dysfunctional organs.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Puma deletion prolongs lifespan and improves stem- and progenitor-cell-based organ maintenance of telomere-dysfunctional mice.
Figure 2: Puma deletion reduces apoptosis in stem and progenitor cells with dysfunctional telomeres.
Figure 3: Puma deletion accelerates the accumulation of DNA damage and the upregulation of p21 in telomere-dysfunctional stem and progenitor cells.
Figure 4: p21 and Puma represent synergistic checkpoints preventingproliferation and the evolution of chromosomal instability of telomere-dysfunctional stem and progenitor cells.

Similar content being viewed by others

Change history

References

  1. Kujoth, G. C. et al. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 309, 481–484 (2005).

    Article  CAS  Google Scholar 

  2. Rudolph, K. L. et al. Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell 96, 701–712 (1999).

    Article  CAS  Google Scholar 

  3. Hasty, P., Campisi, J., Hoeijmakers, J., van Steeg, H. & Vijg, J. Aging and genome maintenance: lessons from the mouse? Science 299, 1355–1359 (2003).

    Article  CAS  Google Scholar 

  4. Migliaccio, E. et al. The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature 402, 309–313 (1999).

    Article  CAS  Google Scholar 

  5. Hamann, A., Brust, D. & Osiewacz, H. D. Apoptosis pathways in fungal growth, development and ageing. Trends Microbiol. 16, 276–283 (2008).

    Article  CAS  Google Scholar 

  6. Perez, G. I. et al. Prolongation of ovarian lifespan into advanced chronological age by Bax-deficiency. Nat. Genet. 21, 200–203 (1999).

    Article  CAS  Google Scholar 

  7. Chin, L. et al. p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell 97, 527–538 (1999).

    Article  CAS  Google Scholar 

  8. Begus-Nahrmann, Y. et al. p53 deletion impairs clearance of chromosomal-instable stem cells in aging telomere-dysfunctional mice. Nat. Genet. 41, 1138–1143 (2009).

    Article  CAS  Google Scholar 

  9. Erlacher, M. et al. BH3-only proteins Puma and Bim are rate-limiting for gamma-radiation- and glucocorticoid-induced apoptosis of lymphoid cells in vivo. Blood 106, 4131–4138 (2005).

    Article  CAS  Google Scholar 

  10. Jeffers, J. R. et al. Puma is an essential mediator of p53-dependent and -independent apoptotic pathways. Cancer Cell 4, 321–328 (2003).

    Article  CAS  Google Scholar 

  11. Villunger, A. et al. p53- and drug-induced apoptotic responses mediated by BH3-only proteins puma and noxa. Science 302, 1036–1038 (2003).

    Article  CAS  Google Scholar 

  12. Wu, W. S. et al. Slug antagonizes p53-mediated apoptosis of hematopoietic progenitors by repressing puma. Cell 123, 641–653 (2005).

    Article  CAS  Google Scholar 

  13. Michalak, E. M., Villunger, A., Adams, J. M. & Strasser, A. In several cell types tumour suppressor p53 induces apoptosis largely via Puma but Noxa can contribute. Cell Death Differ. 15, 1019–1029 (2008).

    Article  CAS  Google Scholar 

  14. Liu, D. et al. Puma is required for p53-induced depletion of adult stem cells. Nat. Cell Biol. 12, 993–998 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Blasco, M. A. et al. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 91, 25–34 (1997).

    Article  CAS  Google Scholar 

  16. Choudhury, A. R. et al. Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation. Nat. Genet. 39, 99–105 (2007).

    Article  CAS  Google Scholar 

  17. Schaetzlein, S. et al. Exonuclease-1 deletion impairs DNA damage signaling and prolongs lifespan of telomere-dysfunctional mice. Cell 130, 863–877 (2007).

    Article  CAS  Google Scholar 

  18. Wong, K. K. et al. Telomere dysfunction and Atm deficiency compromises organ homeostasis and accelerates ageing. Nature 421, 643–648 (2003).

    Article  CAS  Google Scholar 

  19. van der Flier, L. G. et al. Transcription factor achaete scute-like 2 controls intestinal stem cell fate. Cell 136, 903–912 (2009).

    Article  CAS  Google Scholar 

  20. Sato, T. et al. Single Lgr5 stem cells build crypt–villus structures in vitro without a mesenchymal niche. Nature 459, 262–265 (2009).

    Article  CAS  Google Scholar 

  21. Kirk, K. E., Harmon, B. P., Reichardt, I. K., Sedat, J. W. & Blackburn, E. H. Block in anaphase chromosome separation caused by a telomerase template mutation. Science 275, 1478–1481 (1997).

    Article  CAS  Google Scholar 

  22. Rudolph, K. L., Millard, M., Bosenberg, M. W. & DePinho, R. A. Telomere dysfunction and evolution of intestinal carcinoma in mice and humans. Nat. Genet. 28, 155–159 (2001).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  24. Cheng, H. & Leblond, C. P. Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. V. Unitarian Theory of the origin of the four epithelial cell types. Am. J. Anat. 141, 537–561 (1974).

    Article  CAS  Google Scholar 

  25. Potten, C. S. et al. Identification of a putative intestinal stem cell and early lineage marker; musashi-1. Differentiation 71, 28–41 (2003).

    Article  CAS  Google Scholar 

  26. Hastie, N. D. et al. Telomere reduction in human colorectal carcinoma and with ageing. Nature 346, 866–868 (1990).

    Article  CAS  Google Scholar 

  27. Jiang, H. et al. Proteins induced by telomere dysfunction and DNA damage represent biomarkers of human aging and disease. Proc. Natl Acad. Sci. USA 105, 11299–11304 (2008).

    Article  CAS  Google Scholar 

  28. Aggarwal, S. & Gupta, S. Increased apoptosis of T cell subsets in aging humans: altered expression of Fas (CD95), Fas ligand, Bcl-2, and Bax. J. Immunol. 160, 1627–1637 (1998).

    CAS  PubMed  Google Scholar 

  29. Ciccocioppo, R. et al. Small bowel enterocyte apoptosis and proliferation are increased in the elderly. Gerontology 48, 204–208 (2002).

    Article  CAS  Google Scholar 

  30. Hashimoto, S., Ochs, R. L., Komiya, S. & Lotz, M. Linkage of chondrocyte apoptosis and cartilage degradation in human osteoarthritis. Arthritis Rheum. 41, 1632–1638 (1998).

    Article  CAS  Google Scholar 

  31. Mustata, G. et al. Development of small-molecule PUMA inhibitors for mitigating radiation-induced cell death. Curr. Top. Med. Chem. 11, 281–290.

    Article  CAS  Google Scholar 

  32. Wiemann, S. U. et al. Hepatocyte telomere shortening and senescence are general markers of human liver cirrhosis. FASEB J. 16, 935–942 (2002).

    Article  CAS  Google Scholar 

  33. Armanios, M. Y. et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. N. Engl. J. Med. 356, 1317–1326 (2007).

    Article  CAS  Google Scholar 

  34. Ohyashiki, J. H. et al. Telomere shortening associated with disease evolution patterns in myelodysplastic syndromes. Cancer Res. 54, 3557–3560 (1994).

    CAS  PubMed  Google Scholar 

  35. Herrera, E. et al. Disease states associated with telomerase deficiency appear earlier in mice with short telomeres. EMBO J. 18, 2950–2960 (1999).

    Article  CAS  Google Scholar 

  36. Geigl, J. B. & Speicher, M. R. Single-cell isolation from cell suspensions and whole genome amplification from single cells to provide templates for CGH analysis. Nat. Protoc. 2, 3173–3184 (2007).

    Article  CAS  Google Scholar 

  37. van Beers, E. H. et al. A multiplex PCR predictor for aCGH success of FFPE samples. Br. J. Cancer 94, 333–337 (2006).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank G. Zambetti for providing P u m a−/− mice, C. Kuo for the R-spondin construct and H. Clevers for discussions. The Deutsche Forschungsgemeinschaft (Klinische Forschergruppe 142 & 167 and Ru745/10) and the European Union (GENINCA) supported this work.

Author information

Author notes

  1. Zhangfa Song

    Present address: Present address: Department of Colorectal Surgery, Sir Run Run Shaw Hospital, 3 East Qingchun Road, 310016, Hangzhou, China,

Authors and Affiliations

  1. Institute of Molecular Medicine and Max-Planck-Research Department on Stem Cell Aging, University of Ulm, 89081 Ulm, Germany

    Tobias Sperka, Zhangfa Song, Yohei Morita, Kodandaramireddy Nalapareddy, Luis Miguel Guachalla, André Lechel, Yvonne Begus-Nahrmann, Martin D. Burkhalter & K. Lenhard Rudolph

  2. Institute of Human Genetics, Medical University of Graz, Harrachgasse 21/8, A-8010 Graz, Austria

    Monika Mach & Michael R. Speicher

  3. Institute of Applied Physiology, University of Ulm, 89081 Ulm, Germany

    Falk Schlaudraff & Birgit Liss

  4. Institute of Aging Research, Hangzhou Normal University College of Medicine, 16 Xuelin Road, 310036, Hangzhou, China

    Zhenyu Ju

Authors
  1. Tobias Sperka
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhangfa Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yohei Morita
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kodandaramireddy Nalapareddy
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Luis Miguel Guachalla
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. André Lechel
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yvonne Begus-Nahrmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Martin D. Burkhalter
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Monika Mach
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Falk Schlaudraff
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Birgit Liss
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Zhenyu Ju
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Michael R. Speicher
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. K. Lenhard Rudolph
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

T.S., Z.S., Y.M., K.N., Y.B-N., M.D.B. and Z.J. carried out, designed and analysed experiments; T.S., A.L., Y.B-N., M.M. and M.R.S. carried out and analysed aCGH experiments; F.S. and B.L. carried out microdissection; Z.S. and L.M.G. generated mouse crosses; K.L.R. and T.S. wrote the manuscript; K.L.R. conceived the study.

Corresponding author

Correspondence to K. Lenhard Rudolph.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Information (PDF 1774 kb)

Supplementary Tables 1–3

Supplementary Information (XLS 38 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sperka, T., Song, Z., Morita, Y. et al. Puma and p21 represent cooperating checkpoints limiting self-renewal and chromosomal instability of somatic stem cells in response to telomere dysfunction. Nat Cell Biol 14, 73–79 (2012). https://doi.org/10.1038/ncb2388

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb2388

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