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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.

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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.

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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).

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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
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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.

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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

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