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 (Trf1Δ/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 Trf1Δ/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.
Highlights
Telomere dysfunction is caused by either critical telomere shortening or loss of the protein complex that protects telomeres, the so-called shelterin
Dysfunctional telomeres behave as double strand breaks (DSBs) and trigger a persistent DNA damage response (DDR) (d’Adda di Fagagna et al, 2003; de Lange, 2005a)
Ataxia telangiectasia mutated (ATM) has an essential role in signaling from DSBs arising from ionizing radiation (IR) through a Checkpoint kinase 2 (CHK2)-dependent pathway, while ATR is typically involved in signaling from replication-linked SSBs through the CHK1 kinase
Summary
Telomere dysfunction is caused by either critical telomere shortening or loss of the protein complex that protects telomeres, the so-called shelterin (de Lange, 2005a). Ataxia telangiectasia mutated (ATM) and ATM and Rad-3-related (ATR) protein kinases are among the earliest signaling molecules known to initiate the transduction cascade at damage sites. This cascade results in the activation of p21 and p53, leading to senescence/apoptosis (Takai et al, 2003; von Zglinicki et al, 2005). Recent findings have demonstrated an active cross talk between ATM and ATR signaling pathways in response to DNA damage (Matsuoka et al, 2000; Murga et al, 2009). Both CHK1 and CHK2 can activate p53 upon DNA damage (Shieh et al, 2000) and are important for cell cycle checkpoints, while CHK1 is crucial for intra-S and G2/S transition, CHK2 is more important for G1/S checkpoint (Liu et al, 2000; Takai et al, 2000, 2002; Hirao et al, 2002)
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