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 language | English |
|---|---|
| Pages (from-to) | 99-105 |
| Number of pages | 7 |
| Journal | Nature Genetics |
| Volume | 39 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 2007 Jan 1 |
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All Science Journal Classification (ASJC) codes
- Genetics
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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 journal › Article
TY - JOUR
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=33845892109&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33845892109&partnerID=8YFLogxK
U2 - 10.1038/ng1937
DO - 10.1038/ng1937
M3 - Article
C2 - 17143283
AN - SCOPUS:33845892109
VL - 39
SP - 99
EP - 105
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 1
ER -