Open AccessIn vivo role of checkpoint kinase 2 in signaling telomere dysfunction
Author(s) -
GarcíaBeccaria María,
Martínez Paula,
Flores Juana M.,
Blasco Maria A.
Publication year - 2014
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12237
Subject(s) - biology , telomere , g2 m dna damage checkpoint , in vivo , kinase , cancer research , checkpoint kinase 2 , genetics , signal transduction , chek1 , microbiology and biotechnology , protein serine threonine kinases , cell cycle checkpoint , cell cycle , dna , cancer , protein kinase a
Summary Checkpoint kinase 2 ( CHK 2) is a downstream effector of the DNA damage response ( DDR ). Dysfunctional telomeres, either owing to critical shortening or disruption of the shelterin complex, activate a DDR , which eventually results in cell cycle arrest, senescence and/or apoptosis. Successive generations of telomerase‐deficient ( T erc ) mice show accelerated aging and shorter lifespan due to tissue atrophy and impaired organ regeneration associated to progressive telomere shortening. In contrast, mice deficient for the shelterin component TRF 1 in stratified epithelia show a rapid and massive induction of DDR , leading to perinatal lethality and severe skin defects. In both mouse models, p53 deficiency can rescue survival. Here, we set to address the role of CHK 2 in signaling telomere dysfunction in both mouse models. To this end, we generated mice doubly deficient for C hk2 and either T erc ( C hk2 −/−T erc −/− ) or T rf1 ( T rf1 Δ/ΔK 5 C re C hk2 −/− ). We show that C hk2 deletion improves T erc ‐associated phenotypes, including lifespan and age‐associated pathologies. Similarly, C hk2 deficiency partially rescues perinatal mortality and attenuates degenerative pathologies of T rf1 Δ/Δ K5 C re mice. In both cases, we show that the effects are mediated by a significant attenuation of p53/p21 signaling pathway. Our results represent the first demonstration of a role for CHK 2 in the in vivo signaling of dysfunctional telomeres.