Increased telomere fragility and fusions resulting from TRF1 deficiency lead to degenerative pathologies and increased cancer in mice

Abstract

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 g-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 D/D 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.[Keywords: Telomeres; TRF1; DNA damage; chromosomal instability; conditional knockout mice; cancer] Supplemental material is available at http://www.genesdev.org.

Human Stn1 protects telomere integrity by promoting efficient lagging-strand synthesis at telomeres and mediating C-strand fill-in

“…These features pose challenges to replication machinery, and replication forks are vulnerable to stalling at telomeric tracts [23,24]. This is validated by recent reports demonstrating that telomeres resemble common fragile sites and efficient replication of telomeric DNA requires assistance from telomerebinding proteins as well as associated factors [25][26][27][28][29][30].…”

Mice with reduced expression of the telomere‐associated protein Ft1 develop p53‐sensitive progeroid traits

“…Ft1 kof/kof mice displayed multiple traits that have been previously observed in several progeroid models (Table S2). We found that Ft1 mutant mice have reduced body weight, fertility defects, and reduced lifespan, as previously observed in models of laminopathies (Bergo et al., 2002; Osorio, Navarro, et al., 2011) and telomeropathies (Martínez et al., 2009). In addition, the growth defects of Ft1 kof/kof mice were exacerbated with aging, suggesting that the effects of Ft1 mutations intercept the normal aging‐induced degeneration pathways.…”

“…In addition, the growth defects of Ft1 kof/kof mice were exacerbated with aging, suggesting that the effects of Ft1 mutations intercept the normal aging‐induced degeneration pathways. Ft1 kof/kof mice also displayed skin and bone defects, which were previously observed in lamin mutant mice (Bergo et al., 2002; Mounkes et al., 2003; Osorio, Navarro, et al., 2011), in Tert ko animals (Rudolph et al., 1999), and in mice with reduced Trf1 expression (Martínez et al., 2009). Skeletal alterations and lipodystrophy have been imputed to failures in the proliferation of mesenchymal stem cell progenitors, which are sensitive to lamin mutations and senescence (Scaffidi & Misteli, 2008).…”

Rint1 inactivation triggers genomic instability, ER stress and autophagy inhibition in the brain

“…Anaphase bridges are found among cells exhibiting impaired telomere homeostasis [39][40][41][42] and defective DNA DSB repair. [36][37][38][39][40][41][42][43][44][45][46][47][48][49] RINT1 is known to be involved in both pathways through interaction with p130 15 or Rad50. 14 The structure of chromosome fusion in the Rint1-deficient cells supports the hypothesis of defective DSB repair (Figures 4c and d).…”