The telomere repeat-binding factor 1 (
TERF1, referred to hereafter as TRF1) is a component of mammalian telomeres whose role in telomere biology and disease has remained elusive. Here, we report on cells and
mice conditionally deleted for TRF1. TRF1-deleted
mouse embryonic fibroblasts (MEFs) show rapid induction of
senescence, which is
concomitant with abundant telomeric gamma-H2AX foci and
activation of the ATM/ATR downstream checkpoint
kinases CHK1 and
CHK2.
DNA damage foci are rescued by both ATM and ATM/ATR inhibitors, further indicating that both
signaling pathways are activated upon TRF1 deletion. Abrogation of the p53 and RB pathways bypasses
senescence but leads to
chromosomal instability including
sister chromatid fusions,
chromosome concatenation, and occurrence of multitelomeric signals (MTS). MTS are also elevated in ATR-deficient MEFs or upon treatment with
aphidicolin, two conditions known to induce breakage at
fragile sites, suggesting that TRF1-depleted telomeres are
prone to breakage. To address the impact of these molecular defects in the organism, we deleted TRF1 in stratified
epithelia of TRF1(Delta/Delta)K5-Cre
mice. These
mice die perinatally and show
skin hyperpigmentation and
epithelial dysplasia, which are associated with induction of telomere-instigated
DNA damage,
activation of the p53/p21 and p16 pathways, and
cell cycle arrest in vivo. p53 deficiency rescues
mouse survival but leads to development of
squamous cell carcinomas, demonstrating that TRF1 suppresses
tumorigenesis. Together, these results demonstrate that dysfunction of a telomere-binding protein is sufficient to produce severe telomeric damage in the absence of telomere
shortening, resulting in premature tissue degeneration and development of
neoplastic lesions.
