Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation.
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.
Choudhury
Aaheli Roy
AR
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
Ju
Zhenyu
Z
Djojosubroto
Meta W
MW
Schienke
Andrea
A
Lechel
Andre
A
Schaetzlein
Sonja
S
Jiang
Hong
H
Stepczynska
Anna
A
Wang
Chunfang
C
Buer
Jan
J
Lee
Han-Woong
HW
von Zglinicki
Thomas
T
Ganser
Arnold
A
Schirmacher
Peter
P
Nakauchi
Hiromitsu
H
Rudolph
K Lenhard
KL
D000818:Animals; D002478:Cells, Cultured; D003433:Crosses, Genetic; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics*; D018450:Disease Progression; D017353:Gene Deletion; D007422:Intestines / Q000166:cytology; D008136:Longevity / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D013234:Stem Cells / Q000502:physiology*; D019098:Telomerase / Q000235:genetics; D016615:Telomere / Q000502:physiology*
C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D019098:Telomerase