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  • The telomere deprotection response is functionally distinct from the genomic DNA damage response. 23850488

    Loss of chromosome end protection through telomere erosion is a hallmark of aging and senescence. Here we developed an experimental system that mimics physiological telomere deprotection in human cells and discovered that the telomere deprotection response is functionally distinct from the genomic DNA damage response. We found that, unlike genomic breaks, deprotected telomeres that are recognized as DNA damage but remain in the fusion-resistant intermediate state activate differential ataxia telangiectasia mutated (ATM) signaling where CHK2 is not phosphorylated. Also unlike genomic breaks, we found that deprotected telomeres do not contribute to the G2/M checkpoint and are instead passed through cell division to induce p53-dependent G1 arrest in the daughter cells. Telomere deprotection is therefore an epigenetic signal passed between cell generations to ensure that replication-associated telomere-dependent growth arrest occurs in stable diploid G1 phase cells before genome instability can occur.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple

  • Telomere elongation in induced pluripotent stem cells from dyskeratosis congenita patients. 20164838

    Patients with dyskeratosis congenita (DC), a disorder of telomere maintenance, suffer degeneration of multiple tissues. Patient-specific induced pluripotent stem (iPS) cells represent invaluable in vitro models for human degenerative disorders like DC. A cardinal feature of iPS cells is acquisition of indefinite self-renewal capacity, which is accompanied by induction of the telomerase reverse transcriptase gene (TERT). We investigated whether defects in telomerase function would limit derivation and maintenance of iPS cells from patients with DC. Here we show that reprogrammed DC cells overcome a critical limitation in telomerase RNA component (TERC) levels to restore telomere maintenance and self-renewal. We discovered that TERC upregulation is a feature of the pluripotent state, that several telomerase components are targeted by pluripotency-associated transcription factors, and that in autosomal dominant DC, transcriptional silencing accompanies a 3' deletion at the TERC locus. Our results demonstrate that reprogramming restores telomere elongation in DC cells despite genetic lesions affecting telomerase, and show that strategies to increase TERC expression may be therapeutically beneficial in DC patients.
    Document Type:
    Reference
    Product Catalog Number:
    07-449
    Product Catalog Name:
    Anti-trimethyl-Histone H3 (Lys27) Antibody

  • Telomere length influences cancer cell differentiation in vivo. 23716593

    Limitless reproductive potential is one of the hallmarks of cancer cells. This ability is due to the maintenance of telomeres, erosion of which causes cellular senescence or death. While most cancer cells activate telomerase, a telomere-elongating enzyme, it remains elusive as to why cancer cells often maintain shorter telomeres than the cells in the surrounding normal tissues. Here, we show that forced telomere elongation in cancer cells promotes their differentiation in vivo. We elongated the telomeres of human prostate cancer cells that possess short telomeres by enhancing their telomerase activity. The resulting cells had long telomeres and retained the ability to form tumors in nude mice. Strikingly, these tumors exhibited many duct-like structures and reduced N-cadherin expression, reminiscent of well-differentiated adenocarcinoma. These changes were caused by telomere elongation and not by enhanced telomerase activity. Gene expression profiling revealed that tumor formation was accompanied by the expression of innate immune system-related genes, which have been implicated in maintaining tumor cells in an undifferentiated state and poor-prognosis cancers. In tumors derived from the telomere-elongated cells, upregulation of such gene sets is not observed. Our observations suggest a functional contribution of short telomeres to tumor malignancy by regulation of cancer cell differentiation.
    Document Type:
    Reference
    Product Catalog Number:
    05-636
    Product Catalog Name:
    Anti-phospho-Histone H2A.X (Ser139) Antibody, clone JBW301

  • Telomere dysfunction in human keratinocytes elicits senescence and a novel transcription profile. 18589416

    The uncapping of telomeres has been shown to precipitate senescence in normal human fibroblasts and apoptosis in lymphocytes and p53-competent cancer cell lines. However, the effects of telomere uncapping on normal epithelial cells have not previously been examined. We have used the well characterised telomere repeat binding factor 2 (TRF2) dominant-negative mutant, TRF2(DeltaBDeltaM), to deplete Normal Human Epidermal Keratinocytes (NHEK) telomeres of TRF2. We observed only a two fold increase in both phosphorylation of p53 at serine 15 and 53BP1 DNA damage foci and no detectable increase in p21(WAF). Despite the weak DNA damage response, the keratinocytes growth arrest, demonstrate reduced colony formation and senescence. The small, abortive senescent colonies did not incorporate Brd-U within 48 h and expressed senescence-associated beta galactosidase (SA-beta-gal). Transcriptional profiling of TRF2-depleted keratinocytes showed a reproducible up-regulation of several genes. These included histones, genes associated with DNA damage and keratinocyte terminal differentiation. Several of the same genes were also shown to be up-regulated when keratinocytes undergo natural telomere-mediated senescence and down-regulated by ectopic telomerase expression. This study has thus revealed highly sensitive and specific candidate indicators of telomere dysfunction that may find use in identifying telomere-mediated keratinocyte senescence in ageing, cancer and other diseases.
    Document Type:
    Reference
    Product Catalog Number:
    05-726
    Product Catalog Name:
    Anti-53BP1 Antibody, clone BP13

  • Telomere maintenance and DNA damage responses during lung carcinogenesis. 20404006

    Telomere shortening is an early event in bronchial carcinogenesis, preceding P53/Rb pathway inactivation and telomerase reactivation, and leading to DNA damage responses (DDR). As their inactivation in cancer increases genetic instability, our objective was to identify the chronology of telomere machinery critical events for malignant progression.
    Document Type:
    Reference
    Product Catalog Number:
    05-636
    Product Catalog Name:
    Anti-phospho-Histone H2A.X (Ser139) Antibody, clone JBW301

  • Telomere shortening is correlated with the DNA damage response and telomeric protein down-regulation in colorectal preneoplastic lesions. 18641004

    A relation between telomere attrition in early carcinogenesis and activation of DNA damage response (DDR) has been proposed. We explored telomere length and its link with DDR in colorectal multistep carcinogenesis.We studied normal mucosa, low-grade dysplasia (LGD) and high-grade dysplasia (HGD) and invasive carcinoma (IC) in matched human colon specimens by evaluating p-ataxia telangiectasia mutated (ATM), p-checkpoint kinase 2 (Chk2), c-H2AX, TRF1 and TRF2 expressions by immunohistochemistry. FISH was used to assess telomere length.Telomeres shortened significantly from normal (N) to LGD and HGD (P less than 0.0001; P = 0.012), then increased in length in IC (P = 0.006). TRF1 and TRF2 expressions were diminished from N to LGD and HGD (P = 0.004, P less than 0.0001, ns) and were reexpressed at the invasive stage (P = 0.053 and P = 0.046). Phosphorylated ATM, Chk2 and H2AX appeared already in LGD (respectively, P = 0.001, P = 0.002 and P = 0.02). Their expression decreased from HGD to IC (respectively, P = 0.03, P = 0.02 and P = 0.37). These activating phosphorylations were inversely correlated with telomere length and TRF1/2 expression.In a model of colon multistep carcinogenesis, our data indicate that telomeric length and protein expression levels are inversely correlated with the activation of the DDR pathway.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple

  • Telomere length regulates TERRA levels through increased trimethylation of telomeric H3K9 and HP1α. 22922742

    Gene silencing by the repressive telomeric chromatin environment, referred to as telomere position effect (TPE), has been well characterized in yeast and depends on telomere length. However, proof of its existence at native human chromosome ends has remained elusive, mainly owing to the paucity of genes near telomeres. The discovery of TERRAs, the telomeric noncoding RNAs transcribed from subtelomeric promoters, paved the way to probing for telomere-length impact on physiological TPE. Using cell lines of various origins, we show that telomere elongation consistently represses TERRA expression. Repression is mediated by increased trimethylated H3K9 density at telomeres and by heterochromatin protein HP1α, with no detectable spreading of the marks beyond the telomeric tract, restricting human TPE to telomere transcription. Our data further support the existence of a negative-feedback mechanism in which longer TERRA molecules repress their own transcription upon telomere elongation.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple