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:

p53 deletion impairs clearance of chromosomal-instable stem cells in aging telomere-dysfunctional mice

Nature Genetics volume 41, pages 1138–1143 (2009)Cite this article

Abstract

Telomere dysfunction limits the proliferative capacity of human cells and induces organismal aging by activation of p53 and p21 (refs. 1, 2, 3, 4, 5, 6). Although deletion of p21 elongates the lifespan of telomere-dysfunctional mice2, a direct analysis of p53 in telomere-related aging has been hampered by early tumor formation in p53 knockout mice6. Here we analyzed the functional consequences of conditional p53 deletion7. Intestinal deletion of p53 shortened the lifespan of telomere-dysfunctional mice without inducing tumor formation. In contrast to p21 deletion, the deletion of p53 impaired the depletion of chromosomal-instable intestinal stem cells in aging telomere-dysfunctional mice. These instable stem cells contributed to epithelial regeneration leading to an accumulation of chromosomal instability, increased apoptosis, altered epithelial cell differentiation and premature intestinal failure. Together, these results provide the first experimental evidence for an organ system in which p53-dependent mechanisms prevent tissue destruction in response to telomere dysfunction by depleting genetically instable stem cells.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: p53 deletion impairs organ maintenance and shortens survival of telomere-dysfunctional mice.
Figure 2: p53 deletion rescues cell cycle arrest but increases apoptosis in telomere-dysfunctional intestine.
Figure 3: p53 deletion increases the accumulation of telomere dysfunction and DNA damage in intestinal epithelium of iG4 mice.
Figure 4: p53 deletion impairs the depletion of stem cells and increases chromosomal instability in basal crypts of telomere-dysfunctional mice.
Figure 5: p53 deletion, but not p21 deletion, increases survival of chromosomal-instable stem cells in basal intestinal crypts of telomere-dysfunctional mice.

Similar content being viewed by others

References

  1. Wright, W.E. & Shay, J.W. The two-stage mechanism controlling cellular senescence and immortalization. Exp. Gerontol. 27, 383–389 (1992).

    Article  CAS  Google Scholar 

  2. 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 

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

    Article  CAS  Google Scholar 

  4. 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 

  5. Hemann, M.T. et al. The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability. Cell 107, 67–77 (2001).

    Article  CAS  Google Scholar 

  6. 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 

  7. Jonkers, J. et al. Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer. Nat. Genet. 29, 418–425 (2001).

    Article  CAS  Google Scholar 

  8. Tyner, S.D. et al. p53 mutant mice that display early ageing-associated phenotypes. Nature 415, 45–53 (2002).

    Article  CAS  Google Scholar 

  9. Garcíía-Cao, I. et al. “Super p53” mice exhibit enhanced DNA damage response, are tumor resistant and age normally. EMBO J. 21, 6225–6235 (2002).

    Article  Google Scholar 

  10. Matheu, A. et al. Delayed ageing through damage protection by the Arf/p53 pathway. Nature 448, 375–379 (2007).

    Article  CAS  Google Scholar 

  11. Tomás-Loba, A. et al. Telomerase reverse transcriptase delays aging in cancer-resistant mice. Cell 135, 609–622 (2008).

    Article  Google Scholar 

  12. 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 

  13. Lieber, M.R. & Karanjawala, Z.E. Ageing, repetitive genomes and DNA damage. Nat. Rev. Mol. Cell Biol. 5, 69–75 (2004).

    Article  CAS  Google Scholar 

  14. Nalapareddy, K. et al. Determining the influence of telomere dysfunction and DNA damage on stem and progenitor cell aging - what markers can we use? Exp. Gerontol. 43, 998–1004 (2008).

    Article  CAS  Google Scholar 

  15. Brown, J.P., Wei, W. & Sedivy, J.M. Bypass of senescence after disruption of p21CIP1/WAF1 gene in normal diploid human fibroblasts. Science 277, 831–834 (1997).

    Article  CAS  Google Scholar 

  16. García-Cao, I. et al. Increased p53 activity does not accelerate telomere-driven ageing. EMBO Rep. 7, 546–552 (2006).

    PubMed  PubMed Central  Google Scholar 

  17. el Marjou, F. et al. Tissue-specific and inducible Cre-mediated recombination in the gut epithelium. Genesis 39, 186–193 (2004).

    Article  CAS  Google Scholar 

  18. Rudolph, K.L. et al. Telomere dysfunction and evolution of intestinal carcinoma in mice and humans. Nat. Genet. 28, 155–159 (2001).

    Article  CAS  Google Scholar 

  19. 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 

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

    Article  CAS  Google Scholar 

  21. Rando, T.A. Stem cells, ageing and the quest for immortality. Nature 441, 1080–1086 (2006).

    Article  CAS  Google Scholar 

  22. Sharpless, N.E. & DePinho, R.A. How stem cells age and why this makes us grow old. Nat. Rev. Mol. Cell Biol. 8, 703–713 (2007).

    Article  CAS  Google Scholar 

  23. Chambers, S.M. et al. Aging hematopoietic stem cells decline in function and exhibit epigenetic dysregulation. PLoS Biol. 5, e201 (2007).

    Article  Google Scholar 

  24. Riboni, R. et al. Telomeric fusions in cultured human fibroblasts as a source of genomic instability. Cancer Genet. Cytogenet. 95, 130–136 (1997).

    Article  CAS  Google Scholar 

  25. Feng, Z. et al. Declining p53 function in the aging process: a possible mechanism for the increased tumor incidence in older populations. Proc. Natl. Acad. Sci. USA 104, 16633–16638 (2007).

    Article  CAS  Google Scholar 

  26. Komarova, E.A. et al. Dual effect of p53 on radiation sensitivity in vivo: p53 promotes hematopoietic injury, but protects from gastro-intestinal syndrome in mice. Oncogene 23, 3265–3271 (2004).

    Article  CAS  Google Scholar 

  27. Flores, I. & Blasco, M.A. A p53-dependent response limits epidermal stem cell functionality and organismal size in mice with short telomeres. PLoS One 4, e4934 (2009).

    Article  Google Scholar 

  28. Poon, S.S. et al. Telomere length measurements using digital fluorescence microscopy. Cytometry 36, 267–278 (1999).

    Article  CAS  Google Scholar 

  29. Chung, Y.J. et al. A whole-genome mouse BAC microarray with 1-Mb resolution for analysis of DNA copy number changes by array comparative genomic hybridization. Genome Res. 14, 188–196 (2004).

    Article  CAS  Google Scholar 

  30. 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 

  31. 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 S. Robine (Institute Curie-CNRS, Paris) for providing villin-Cre-ERT2 mice and A. Berns (The Netherlands Cancer Institute, Amsterdam) for providing conditional p53 knockout mice. We thank J. Jonkers ((The Netherlands Cancer Institute, Amsterdam ) for providing the BAC clones for chromosome FISH. We thank G. Schütz (German Cancer Research Center, Heidelberg) for providing self-made Cre antibody. We thank C. Günes for critical reading of the manuscript. This project was supported by funding from the Deutsche Forschungsgemeinschaft (KFO 167, RU745/10-1), by the Deutsche Krebshilfe e.V. (consortium grant on tumor stem cells) and by the European Union (GENINCA, Telomarker). K.L.R. and M.R.S. are both supported by the European Union (GENINCA, contract number 202230).

Author information

Authors and Affiliations

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

    Yvonne Begus-Nahrmann, André Lechel, Kodandaramireddy Nalapareddy, Elvira Peit & K Lenhard Rudolph

  2. Institute of Human Genetics, Medical University of Graz, Graz, Austria

    Anna C Obenauf, Eva Hoffmann & Michael R Speicher

  3. Institute of General Physiology, University of Ulm, Ulm, Germany

    Falk Schlaudraff & Birgit Liss

  4. Institute of Pathology, University Hospital, Heidelberg, Germany

    Peter Schirmacher

  5. Institute for Neuroinformatics, University of Ulm, Ulm, Germany

    Hans Kestler

  6. Hubrecht Institute, Utrecht, The Netherlands

    Esther Danenberg, Nick Barker & Hans Clevers

Authors
  1. Yvonne Begus-Nahrmann
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. André Lechel
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Anna C Obenauf
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Kodandaramireddy Nalapareddy
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Elvira Peit
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Eva Hoffmann
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Falk Schlaudraff
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Birgit Liss
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Peter Schirmacher
    View author publications

    You can also search for this author inPubMed Google Scholar

  10. Hans Kestler
    View author publications

    You can also search for this author inPubMed Google Scholar

  11. Esther Danenberg
    View author publications

    You can also search for this author inPubMed Google Scholar

  12. Nick Barker
    View author publications

    You can also search for this author inPubMed Google Scholar

  13. Hans Clevers
    View author publications

    You can also search for this author inPubMed Google Scholar

  14. Michael R Speicher
    View author publications

    You can also search for this author inPubMed Google Scholar

  15. K Lenhard Rudolph
    View author publications

    You can also search for this author inPubMed Google Scholar

Contributions

Y.B.-N. conducted experiments and data analysis; A.L. and E.P. conducted the chromosome FISH; A.C.O., M.R.S. and E.H. conducted array-CGH analysis; K.N. and P.S. did the analysis of intestinal atrophy and pathology; F.S. and B.L. conducted the laser microdissection of intestinal crypts; H.K. was responsible for the bioinformatics; E.D., N.B. and H.C. conducted the OLFM4 in situ; K.L.R. was responsible for the study design and manuscript preparation.

Corresponding author

Correspondence to K Lenhard Rudolph.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–6 and Supplementary Tables 1 and 2 (PDF 1143 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Begus-Nahrmann, Y., Lechel, A., Obenauf, A. et al. p53 deletion impairs clearance of chromosomal-instable stem cells in aging telomere-dysfunctional mice. Nat Genet 41, 1138–1143 (2009). https://doi.org/10.1038/ng.426

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.426

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