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 |
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Pages (from-to) | 99-105 |
Number of pages | 7 |
Journal | Nature Genetics |
Volume | 39 |
Issue number | 1 |
DOIs | |
Publication status | Published - 2007 Jan |
Bibliographical note
Funding Information:We thank P. Leder (Department of Genetics, Harvard Medical School) for providing Cdkn1a knockout mice. We thank R. Greenberg and N. Bardeesy for critical discussion and M. Ballmaier (Cell Sorting Core Facility, Hannover Medical School) for cell sorting. K.L.R. is supported by the Deutsche Forschungsgemeinschaft (Heisenberg Professorship: Ru 745/8-1, Ru745 4-1 and KFO119) and the Deutsche Krebshilfe e.V. (10-2236-Ru 2) as well as the Roggenbuck Foundation, the Wilhelm Sander Foundation and the Fritz Thyssen Foundation. H.W.L. was supported by grants from the 21C Frontier Functional Human Genome Project (FG05-22-02) and the BRC Frontier (M103KV010018-05K2201-01830).
All Science Journal Classification (ASJC) codes
- Genetics