Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation

Aaheli Roy Choudhury, Zhenyu Ju, Meta W. Djojosubroto, Andrea Schienke, Andre Lechel, Sonja Schaetzlein, Hong Jiang, Anna Stepczynska, Chunfang Wang, Jan Buer, Han Woong Lee, Thomas Von Zglinicki, Arnold Ganser, Peter Schirmacher, Hiromitsu Nakauchi, K. Lenhard Rudolph

Research output: Contribution to journalArticle

308 Citations (Scopus)

Abstract

Telomere shortening limits the proliferative lifespan of human cells by activation of DNA damage pathways, including upregulation of the cell cycle inhibitor p21 (encoded by Cdkn1a, also known as Cip1 and Waf1)) (refs. 1-5). Telomere shortening in response to mutation of the gene encoding telomerase is associated with impaired organ maintenance and shortened lifespan in humans and in mice. The in vivo function of p21 in the context of telomere dysfunction is unknown. Here we show that deletion of p21 prolongs the lifespan of telomerase-deficient mice with dysfunctional telomeres. p21 deletion improved hematolymphopoiesis and the maintenance of intestinal epithelia without rescuing telomere function. Moreover, deletion of p21 rescued proliferation of intestinal progenitor cells and improved the repopulation capacity and self-renewal of hematopoietic stem cells from mice with dysfunctional telomeres. In these mice, apoptotic responses remained intact, and p21 deletion did not accelerate chromosomal instability or cancer formation. This study provides experimental evidence that telomere dysfunction induces p21-dependent checkpoints in vivo that can limit longevity at the organismal level.

Original languageEnglish
Pages (from-to)99-105
Number of pages7
JournalNature Genetics
Volume39
Issue number1
DOIs
Publication statusPublished - 2007 Jan 1

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Telomere
Stem Cells
Telomere Shortening
Telomerase
Neoplasms
Maintenance
Chromosomal Instability
Intestinal Mucosa
Hematopoietic Stem Cells
DNA Damage
Cell Cycle
Up-Regulation
Mutation
Genes

All Science Journal Classification (ASJC) codes

  • Genetics

Cite this

Choudhury, A. R., Ju, Z., Djojosubroto, M. W., Schienke, A., Lechel, A., Schaetzlein, S., ... Rudolph, K. L. (2007). Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation. Nature Genetics, 39(1), 99-105. https://doi.org/10.1038/ng1937
Choudhury, Aaheli Roy ; Ju, Zhenyu ; Djojosubroto, Meta W. ; Schienke, Andrea ; Lechel, Andre ; Schaetzlein, Sonja ; Jiang, Hong ; Stepczynska, Anna ; Wang, Chunfang ; Buer, Jan ; Lee, Han Woong ; Von Zglinicki, Thomas ; Ganser, Arnold ; Schirmacher, Peter ; Nakauchi, Hiromitsu ; Rudolph, K. Lenhard. / Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation. In: Nature Genetics. 2007 ; Vol. 39, No. 1. pp. 99-105.
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Choudhury, AR, Ju, Z, Djojosubroto, MW, Schienke, A, Lechel, A, Schaetzlein, S, Jiang, H, Stepczynska, A, Wang, C, Buer, J, Lee, HW, Von Zglinicki, T, Ganser, A, Schirmacher, P, Nakauchi, H & Rudolph, KL 2007, 'Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation', Nature Genetics, vol. 39, no. 1, pp. 99-105. https://doi.org/10.1038/ng1937

Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation. / Choudhury, Aaheli Roy; Ju, Zhenyu; Djojosubroto, Meta W.; Schienke, Andrea; Lechel, Andre; Schaetzlein, Sonja; Jiang, Hong; Stepczynska, Anna; Wang, Chunfang; Buer, Jan; Lee, Han Woong; Von Zglinicki, Thomas; Ganser, Arnold; Schirmacher, Peter; Nakauchi, Hiromitsu; Rudolph, K. Lenhard.

In: Nature Genetics, Vol. 39, No. 1, 01.01.2007, p. 99-105.

Research output: Contribution to journalArticle

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T1 - Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation

AU - Choudhury, Aaheli Roy

AU - Ju, Zhenyu

AU - Djojosubroto, Meta W.

AU - Schienke, Andrea

AU - Lechel, Andre

AU - Schaetzlein, Sonja

AU - Jiang, Hong

AU - Stepczynska, Anna

AU - Wang, Chunfang

AU - Buer, Jan

AU - Lee, Han Woong

AU - Von Zglinicki, Thomas

AU - Ganser, Arnold

AU - Schirmacher, Peter

AU - Nakauchi, Hiromitsu

AU - Rudolph, K. Lenhard

PY - 2007/1/1

Y1 - 2007/1/1

N2 - Telomere shortening limits the proliferative lifespan of human cells by activation of DNA damage pathways, including upregulation of the cell cycle inhibitor p21 (encoded by Cdkn1a, also known as Cip1 and Waf1)) (refs. 1-5). Telomere shortening in response to mutation of the gene encoding telomerase is associated with impaired organ maintenance and shortened lifespan in humans and in mice. The in vivo function of p21 in the context of telomere dysfunction is unknown. Here we show that deletion of p21 prolongs the lifespan of telomerase-deficient mice with dysfunctional telomeres. p21 deletion improved hematolymphopoiesis and the maintenance of intestinal epithelia without rescuing telomere function. Moreover, deletion of p21 rescued proliferation of intestinal progenitor cells and improved the repopulation capacity and self-renewal of hematopoietic stem cells from mice with dysfunctional telomeres. In these mice, apoptotic responses remained intact, and p21 deletion did not accelerate chromosomal instability or cancer formation. This study provides experimental evidence that telomere dysfunction induces p21-dependent checkpoints in vivo that can limit longevity at the organismal level.

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