Targeting Assay To Study the <i>cis</i> Functions of Human Telomeric Proteins: Evidence for Inhibition of Telomerase by TRF1 and for Activation of Telomere Degradation by TRF2

Ancelin, Katia; Brunori, Michèle; Bauwens, Serge; Koering, Catherine; Brun, Catherine; Ricoul, Michelle; Pommier, Jean-Patrick; Sabatier, Laure; Gilson, Éric

doi:10.1128/mcb.22.10.3474-3487.2002

Cited by 182 publications

(179 citation statements)

References 83 publications

(107 reference statements)

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“…As expected (Ancelin et al, 2002;Karlseder et al, 2002;Wang et al, 2004), full length M-TRF2 and to a much greater extent the M-TRF2 DB protein induce telomere shortening upon cell growth (Supplementary Figure 2). Notably, M-TRF2 DB -expressing cells show an increase in the number of very short telomeres, as deduced from the large smear observed in the telomere length blot (Supplementary Figure 2).…”

Section: Induction Of Different Types Of Trf2 Dysfunction In Telomerisupporting

confidence: 73%

TRF2 inhibition promotes anchorage-independent growth of telomerase-positive human fibroblasts

et al. 2005

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Although telomere instability is observed in human tumors and is associated with the development of cancers in mice, it has yet to be established that it can contribute to the malignant transformation of human cells. We show here that in checkpoint-compromised telomerase-positive human fibroblasts an episode of TRF2 inhibition promotes heritable changes that increase the ability to grow in soft agar, but not tumor growth in nude mice. This transforming activity is associated to a burst of telomere instability but is independent of an altered control of telomere length. Moreover, it cannot be recapitulated by an increase in chromosome breaks induced by an exposure to cradiations. Since it can be revealed in the context of telomerase-proficient human cells, telomere dysfunction might contribute to cancer progression even at late stages of the oncogenesis process, after the telomerase reactivation step.

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Section: Induction Of Different Types Of Trf2 Dysfunction In Telomerisupporting

confidence: 73%

TRF2 inhibition promotes anchorage-independent growth of telomerase-positive human fibroblasts

et al. 2005

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“…31 Thus, although we cannot rule out the possibility that telomere shortening occurred as a result of a remote proliferative burst in the ductal epithelium (perhaps during repeated episodes of injury and repair), it seems to be independent of ongoing proliferation. The genesis of telomere shortening in PanIN lesions remains a matter of speculation; postulated mechanisms include a role for reactive oxidant species, 32 or inactivation of one or more telomere-binding proteins that maintain telomere lengths, [33][34][35] and additional studies may be able to elucidate this issue further.…”

Section: Discussionmentioning

confidence: 99%

Telomere Shortening Is Nearly Universal in Pancreatic Intraepithelial Neoplasia

Heek

Meeker

Kern

et al. 2002

The American Journal of Pathology

321

213

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A multistep model of carcinogenesis has recently been proposed for pancreatic ductal adenocarcinomas. In this model, noninvasive precursor lesions in the pancreatic ductules accumulate genetic alterations in cancer-associated genes eventually leading to the development of an invasive cancer. The nomenclature for these precursor lesions has been standardized as pancreatic intraepithelial neoplasia or PanIN. Despite the substantial advances made in understanding the biology of invasive pancreatic adenocarcinomas, little is known about the initiating genetic events in the pancreatic ductal epithelium that facilitates its progression to cancer. Telomeres are distinctive structures at the ends of chromosomes that protect against chromosomal breakage-fusion-bridge cycles in dividing cells. Critically shortened telomeres can cause chromosomal instability, a sine qua non of most human epithelial cancers. Although evidence for telomeric dysfunction has been demonstrated in invasive pancreatic cancer, the onset of this phenomenon has not been elucidated in the context of noninvasive precursor lesions. We used a recently de- The 5-year survival rate of patients with ductal adenocarcinoma of the pancreas is 4%, one of the lowest of any neoplasm. Each year, nearly 29,000 patients are diagnosed with pancreatic cancer in the United States, and almost all will succumb to their disease.

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“…This regulation process is set on the number of binding sites for telomeric doublestranded DNA-binding proteins in yeast (30) and in mammals (1). In this cis-acting regulation mechanism, more binding sites for TRF1 inhibit telomerase-mediated elongation, whereas more TRF2-binding sites stimulate nuclease-mediated shortening (1,23).…”

Section: Discussionmentioning

confidence: 99%

Dynamics of Protein Binding to Telomeres in Living Cells: Implications for Telomere Structure and Function

Mattern¹,

Swiggers²,

Nigg

et al. 2004

Molecular and Cellular Biology

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Telomeric proteins have an essential role in the regulation of the length of the telomeric DNA tract and in protection against end-to-end chromosome fusion. Telomere organization and how individual proteins are involved in different telomere functions in living cells is largely unknown. By using green fluorescent protein tagging and photobleaching, we investigated in vivo interactions of human telomeric DNA-binding proteins with telomeric DNA. Our results show that telomeric proteins interact with telomeres in a complex dynamic fashion: TRF2, which has a dual role in chromosome end protection and telomere length homeostasis, resides at telomeres in two distinct pools. One fraction (ϳ73%) has binding dynamics similar to TRF1 (residence time of ϳ44 s). Interestingly, the other fraction of TRF2 binds with similar dynamics as the putative end-protecting factor hPOT1 (residence time of ϳ11 min). Our data support a dynamic model of telomeres in which chromosome end-protection and telomere length homeostasis are governed by differential binding of telomeric proteins to telomeric DNA.

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Targeting Assay To Study the cis Functions of Human Telomeric Proteins: Evidence for Inhibition of Telomerase by TRF1 and for Activation of Telomere Degradation by TRF2

Cited by 182 publications

References 83 publications

TRF2 inhibition promotes anchorage-independent growth of telomerase-positive human fibroblasts

TRF2 inhibition promotes anchorage-independent growth of telomerase-positive human fibroblasts

Telomere Shortening Is Nearly Universal in Pancreatic Intraepithelial Neoplasia

Dynamics of Protein Binding to Telomeres in Living Cells: Implications for Telomere Structure and Function

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