Oxidative stress induced telomere instability/damage drives T cell dysfunction in cancer
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PROVIDER: PRJNA1057824 | ENA |
REPOSITORIES: ENA
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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
Project description:The tumor microenvironment imposes immunologic and metabolic stresses sufficient to deviate immune cell differentiation into dysfunctional fates like exhaustion. Our data show that dysfunctional T cells in cancer do not harbor short telomeres indicative of replicative senescence, but rather harbor damaged telomeres, which we hypothesized arose from oxidative stress. Chemo-optogenetic induction of localized mitochondrial or telomeric reactive oxygen species (ROS) using a novel photosensitizer caused DNA damage at telomeres and was sufficient to drive a dysfunctional state in newly activated T cells, with diminished capability for cytokine production. Localizing the ROS scavenger GPX1 directly to telomeres reduced telomere fragility in tumors and improved the function of therapeutic T cells. Protecting telomeres through expression of a telomere-targeted antioxidant protein may preserve T cell function in the tumor microenvironment and drive superior responses to adoptive cell therapies.
2025-09-15 | GSE252120 | GEO
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:The evolutionarily conserved POT1 protein binds the single stranded G-rich telomeric DNA and has been implicated in telomeric DNA maintenance and the suppression of DNA damage checkpoint signaling. Here, we explore human POT1 function through genetics and proteomics discovering that the complete absence of POT1 leads to severe telomere maintenance defects that had not been anticipated from previous depletion studies. We determine the telomeric proteome upon POT1-loss by implementing an improved telomeric chromatin isolation protocol. Using quantitative proteomics by tandem mass tags (TMT) we identified a large set of proteins involved in nucleic acid metabolism that engage with telomeres upon loss of POT1. Inactivation of the homology directed repair machinery suppresses POT1-loss mediated telomeric DNA defects. Our results unravel as major function of human POT1 the suppression of telomere instability induced by homology directed repair.
2020-10-21 | PXD016826 | Pride
Project description:Oxidative DNA damage is likely to be involved in the etiology of cancer and is thought to accelerate tumorigenesis via increased mutation rates. However, the majority of malignant cells acquire a specific type of genomic instability characterized by large-scale genomic rearrangements, defined as chromosomal instability (CIN). The molecular mechanisms underlying CIN are largely unknown. We utilized Saccharomyces cerevisiae as a model system to delineate the relationship between genotoxic stress and CIN. It was found that elevated levels of chronic, unrepaired oxidative DNA damage cause chromosomal aberrations at remarkably high frequencies under both selective and non-selective growth conditions. In this system, exceeding the cellular capacity to appropriately manage oxidative DNA damage results in a “gain of CIN” phenotype and leads to profound karyotypic diversification. These results illustrate a novel mechanism for genome destabilization, which is likely to be relevant to human carcinogenesis. Keywords: CGH-array
2008-02-10 | GSE10152 | GEO
Project description:Abstract: Inflammatory bowel disease (IBD) is a chronic inflammatory condition driven by diverse genetic and nongenetic programs that converge to disrupt immune homeostasis in the intestine. We have reported that, in murine intestinal epithelium with telomere dysfunction, DNA damage-induced activation of ataxia-telangiectasia mutated (ATM) results in ATM-mediated phosphorylation and activation of the YAP1 transcriptional coactivator, which in turn up-regulates pro-IL-18, a pivotal immune regulator in IBD pathogenesis. Moreover, individuals with germline defects in telomere maintenance genes experience increased occurrence of intestinal inflammation and show activation of the ATM/YAP1/pro-IL-18 pathway in the intestinal epithelium. Here, we sought to determine the relevance of the ATM/YAP1/pro-IL-18 pathway as a potential driver of IBD, particularly older-onset IBD. Analysis of intestinal biopsy specimens and organoids from older-onset IBD patients documented the presence of telomere dysfunction and activation of the ATM/YAP1/ precursor of interleukin 18 (pro-IL-18) pathway in the intestinal epithelium. Employing intestinal organoids from healthy individuals, we demonstrated that experimental induction of telomere dysfunction activates this inflammatory pathway.
2021-10-30 | GSE182424 | GEO
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:Renal tubular epithelial cells (TECs) are critical mediators of renal fibrogenesis. Telomere dysfunction has been associated with renal injury and fibrosis. However, the role of telomere dysfunction specifically in TECs in the onset and progression of renal fibrosis remains poorly understood. To investigate the impact of telomere dysfunction on renal injury and fibrosis, we generated mice depleted for the shelterin component TRF1 specifically in TECs. Genetic ablation of Trf1 caused decline in renal function, tubular injury and tubulointerstitial fibrosis eight weeks after TRF1 depletion, concomitant with excessive accumulation of extracellular matrix (ECM), cell cycle arrest at G2/M phase, and telomeric damage. Trf1Δ/Δ mice activated regenerative repair mechanism, increasing the risk of of chronic kidney disease (CKD) progression following acute kidney injury (AKI), supporting proliferation-mediated telomere shortening in tubular cells. Mechanistically, Trf1 deletion upregulated Ras–Raf–Mek–Erk, PI3k/Akt/mTOR and p38 pathways. At humane endpoint, Trf1Δ/Δ mice displayed elevated urinary albumin-to-creatinine ratio (uACR), associated with augmented interstitial fibrosis and tubular atrophy eventually leading to CKD. In folic acid (FA)-induced nephropathy, depletion of Trf1 in TECs mitigated the fibrogenic phenotype of CKD. Collectively, our study underlies the important role of TECs in the development and progression of renal fibrosis and CKD associated to dysfunctional telomeres.
2025-08-21 | GSE272068 | GEO