Similar Datasets
Project description:In mammals, telomere protection is mediated by the essential protein TRF2, which binds chromosome ends and ensures genome integrity1,2. TRF2 depletion results in end-to-end chromosome fusions in all cell types that have been tested so far. Here we find that TRF2 is dispensable for the proliferation and survival of mouse embryonic stem (ES) cells. Trf2-/- (also known as Terf2) ES cells do not exhibit telomere fusions and can be expanded indefinitely. In response to the deletion of TRF2, ES cells exhibit a muted DNA damage response that is characterized by the recruitment of γH2AX-but not 53BP1-to telomeres. To define the mechanisms that control this unique DNA damage response in ES cells, we performed a CRISPR-Cas9-knockout screen. We found a strong dependency of TRF2-null ES cells on the telomere-associated protein POT1B and on the chromatin remodelling factor BRD2. Co-depletion of POT1B or BRD2 with TRF2 restores a canonical DNA damage response at telomeres, resulting in frequent telomere fusions. We found that TRF2 depletion in ES cells activates a totipotent-like two-cell-stage transcriptional program that includes high levels of ZSCAN4. We show that the upregulation of ZSCAN4 contributes to telomere protection in the absence of TRF2. Together, our results uncover a unique response to telomere deprotection during early development.
| S-EPMC9161009 | biostudies-literature
Project description:TRF2-mediated telomere protection is dispensable in pluripotent stem cells
| PRJNA658273 | ENA
Project description:We used microarrays to analyze the prevalence of signalling induced by acute telomere dysfunction (as induced by TRF2DBDM expression = Dataset 1) and in TERC- compared to TERC+ HCC (Dataset 2). Keywords: acute telomere dysfunction, hepatocellular cancer
2006-07-01 | GSE4627 | GEO
Project description:Telomere dysfunction induces two types of cellular responses: cellular senescence and apoptosis. Here we analyzed the influence of the cellular level of telomere dysfunction and the role of p53 on induction of apoptosis and senescence in mouse liver using the experimental system of adenoviral mediated, transient expression of a dominant negative version of TRF2 (TRF2DBDM). Gene-profiling experiments identified p53-dependent and p53-independent changes in gene expression in response to telomere deprotection and transcription factors potentially regulating these genes.
2006-11-21 | E-MEXP-141 | biostudies-arrayexpress
Project description:The shelterin proteins protect telomeres against activation of the DNA damage checkpoints and recombinational repair. We show here that a dimer of the shelterin subunit TRF2 wraps ? 90 bp of DNA through several lysine and arginine residues localized around its homodimerization domain. The expression of a wrapping-deficient TRF2 mutant, named Top-less, alters telomeric DNA topology, decreases the number of terminal loops (t-loops), and triggers the ATM checkpoint, while still protecting telomeres against non-homologous end joining (NHEJ). In Top-less cells, the protection against NHEJ is alleviated if the expression of the TRF2-interacting protein RAP1 is reduced. We conclude that a distinctive topological state of telomeric DNA, controlled by the TRF2-dependent DNA wrapping and linked to t-loop formation, inhibits both ATM activation and NHEJ. The presence of RAP1 at telomeres appears as a backup mechanism to prevent NHEJ when topology-mediated telomere protection is impaired.
| S-EPMC5001171 | biostudies-literature
Project description:Gas exchange in the mammalian lung occurs in the alveolar sacs lined by epithelial cells that form a barrier allowing effective oxygen diffusion. Telomere syndromes have their most common manifestation in degenerative disease of the alveoli, both pulmonary fibrosis and emphysema. We tested the role of telomere dysfunction by inducing deletion of the telomere binding protein Trf2 in type 2 alveolar epithelial cells (AEC2s) that both express the gene encoding surfactant protein C and constitute the regenerative compartment of the alveolar epithelium. Acquired telomere dysfunction in these cells preferentially induced cellular senescence, and mouse lungs were marked by an inflammatory response even though the telomere dysfunction was restricted to the epithelium. Senescent AECs had altered gene expression that differentially fell in inflammatory cell signaling pathways. Bleomycin challenge was uniformly fatal, and Trf2-depleted cells failed to generate clonal alveolar colonies in vitro. The telomere dysfunction response in AEC2s was in part p53-dependent, and we found evidence of a p53-mediated paracrine survival signal to the mesenchyme. These data indicate that telomere dysfunction in the alveolar epithelium limits its regenerative capacity and is sufficient to induce inflammation. It may thus be a primary driving event in telomere-mediated lung disease. Efforts to restore epithelial regenerative capacity may be an effective approach in a subset of fibrosis and emphysema patients. We studied the gene expression changes in adult type II pneumocytes 7 days after deleting Trf2. Mice carried floxed allele of Trf2 and mTmG reporter allele. Type II pneumocytes were collected by FACs sorting GFP+ cells from lungs 7 days after administering tamoxifen. 6 total samples were analysed. Three were from control samples that were heterozygous for Trf2 and three samples had Trf2 deleted.
2015-04-20 | E-GEOD-56892 | biostudies-arrayexpress
Project description:We performed single-molecule telomere length and telomere fusion analysis in patients at different stages of chronic lymphocytic leukaemia (CLL). Our work identified the shortest telomeres ever recorded in primary human tissue reinforcing the concept that there is significant cell division in CLL. Furthermore, we provide direct evidence that critical telomere shortening, dysfunction and fusion contribute to disease progression. The frequency of short telomeres and fusion events increased with advanced disease, but importantly these were also found in a subset of early-stage patient samples indicating that these events can precede disease progression. Sequence analysis of fusion events isolated from individuals with the shortest telomeres revealed limited numbers of repeats at the breakpoint, sub-telomeric deletion and microhomology. Array-CGH analysis of individuals displaying evidence of telomere dysfunction revealed large-scale genomic rearrangements that were concentrated in the telomeric regions; this was not observed in samples with longer telomeres. Array CGH was undertaken on six individuals (five CLL stage C and one stage A) that displayed evidence of telomere dysfunction, and four (three CLL stage A and one stage B) that displayed longer and apparently stable telomeres.
2010-05-28 | E-GEOD-22016 | biostudies-arrayexpress
Project description:Telomere dysfunction induces Sirtuin repression that drives telomere-dependent disease
| PRJNA517700 | ENA
Project description:Background and Aims: Telomere dysfunction can increase tumor initiation by induction of chromosomal instability, but initiated tumor cells need to reactivate telomerase for genome stabilization and tumor progression. However, this concept has not been proven in vivo since appropriate mouse models were lacking. Here, we analyzed hepatocarcinogenesis (i) in a novel mouse model of inducible telomere dysfunction on a telomerase-proficient background, (ii) in telomerase knockout mice with chronic telomere dysfunction (G3 mTerc-/-), and (iii) in wild-type mice with functional telomeres and telomerase. Transient or chronic telomere dysfunction enhanced the rates of chromosomal aberrations during hepatocarcinogenesis, but only telomerase-proficient mice exhibited significantly increased rates of macroscopic tumor formation and cancer cell proliferation in response to telomere dysfunction. In contrast, telomere dysfunction resulted in pronounced accumulation of DNA damage, cell cycle arrest and apoptosis in telomerase-deficient liver tumors. Together, these data provide the first in vivo evidence that transient telomere dysfunction during early and late stages of tumorigenesis can promote chromosomal instability and carcinogenesis in telomerase-proficient mice in the absence of additional genetic checkpoint defects at germline level. RNA from liver tumors derived from from DEN treated TTD+ mice TTD- mice and RNA from normal liver 48h-72h after doxycycline induced transient telomere dysfunction in TTD+ and TTD- liver were isolated and RNA was extracted. Agilent Mouse 4x44K v2 arrays were used. DNA from liver tumors and corrresponding kidney as control derived from from DEN treated TTD+ mice, TTD- mice and mTERC-/- G3 mice was isolated and extracted using Phenol/Chloroform. Agilent Mouse 4x44K and Mouse 1x244K arrays were used.
2012-03-30 | E-GEOD-36813 | biostudies-arrayexpress
Project description:Background and Aims: Telomere dysfunction can increase tumor initiation by induction of chromosomal instability, but initiated tumor cells need to reactivate telomerase for genome stabilization and tumor progression. However, this concept has not been proven in vivo since appropriate mouse models were lacking. Here, we analyzed hepatocarcinogenesis (i) in a novel mouse model of inducible telomere dysfunction on a telomerase-proficient background, (ii) in telomerase knockout mice with chronic telomere dysfunction (G3 mTerc-/-), and (iii) in wild-type mice with functional telomeres and telomerase. Transient or chronic telomere dysfunction enhanced the rates of chromosomal aberrations during hepatocarcinogenesis, but only telomerase-proficient mice exhibited significantly increased rates of macroscopic tumor formation and cancer cell proliferation in response to telomere dysfunction. In contrast, telomere dysfunction resulted in pronounced accumulation of DNA damage, cell cycle arrest and apoptosis in telomerase-deficient liver tumors. Together, these data provide the first in vivo evidence that transient telomere dysfunction during early and late stages of tumorigenesis can promote chromosomal instability and carcinogenesis in telomerase-proficient mice in the absence of additional genetic checkpoint defects at germline level.
2012-03-31 | GSE36813 | GEO