Role of telomeres in cancer and aging


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Maria A Blasco
Spanish National Cancer Centre (CNIO), Madrid, Spain

Abstract

<p>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 (MEF) show rapid induction of senescence, which is concomitant with abundant telomeric γ-H2AX foci, phosphorylation of ATM and its downstream checkpoint kinases CHK1 and CHK2. Abrogation of the p53 and RB pathways bypasses senescence but leads to widespread chromosomal instability including sister chromatid fusions, chromosome concatenation, and ocurrence of multitelomeric signals (MTS), the later resulting from increased breakage at TRF1-depleted telomeres.  </p><p>TRF1-deleted cells show normal telomere length and increased TERRA transcripts, suggesting that TRF1 is a repressor of telomere transcription. To address the impact of these molecular defects in the organism, we deleted TRF1 in stratified epithelia of <i>TRF1<sup>Δ/Δ</sup>K5-Cre</i> mice. These mice die perinatally and show severe 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 <i>in vivo</i>. p53 deficiency in <i>p53<sup>-/-</sup>/TRF1<sup>Δ/Δ</sup>K5-Cre</i> mice rescues mouse survival but leads to development of squamous cell carcinomas, demonstrating that TRF1 suppresses tumourigenesis. </p><p>Together, these results demonstrate that dysfunction of a telomere binding protein is sufficient to produce severe telomeric damage and loss of telomere capping in the absence of telomere shortening, resulting into premature tissue degeneration, acquisition of chromosomal aberrations and development of neoplastic lesions.</p><br>