title: In vivo role of checkpoint kinase 2 in signaling telomere dysfunction.
abstract: Checkpoint kinase 2 (CHK2) 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 (Terc) 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 TRF1 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 CHK2 in signaling telomere dysfunction in both mouse models. To this end, we generated mice doubly deficient for Chk2 and either Terc (Chk2(-/-) Terc(-/-) ) or Trf1 (Trf1(Δ/Δ) K5Cre Chk2(-/-) ). We show that Chk2 deletion improves Terc-associated phenotypes, including lifespan and age-associated pathologies. Similarly, Chk2 deficiency partially rescues perinatal mortality and attenuates degenerative pathologies of Trf1(Δ/Δ) K5Cre 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 CHK2 in the in vivo signaling of dysfunctional telomeres.
authors.affiliation: Molecular Oncology Program, Telomeres and Telomerase Group, Spanish National Cancer Research Centre (CNIO), Madrid, E-28029, Spain.
authors.forename: María
authors.initials: M
authors.lastname: García-Beccaria
authors.forename: Paula
authors.initials: P
authors.lastname: Martínez
authors.forename: Juana M
authors.initials: JM
authors.lastname: Flores
authors.forename: Maria A
authors.initials: MA
authors.lastname: Blasco
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D049109:Cell Proliferation; D064447:Checkpoint Kinase 2 / Q000378:metabolism*; D004249:DNA Damage; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D015398:Signal Transduction; D016615:Telomere / Q000378:metabolism*
chemical_list: D064447:Checkpoint Kinase 2
keywords: DNA damage; aging; genetics; lifespan; telomerase; telomere