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 journalArticlepeer-review

313 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

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

Fingerprint Dive into the research topics of 'Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation'. Together they form a unique fingerprint.

Cite this