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

Brunori, Michèle; Mathieu, N.; Ricoul, Michelle; Bauwens, Serge; Koering, Catherine; Climens, Aude Roborel de; Belleville, Aurélie; Wang, Q; Puisieux, Isabelle; Décimo, Didier; Puisieux, Alain; Sabatier, Laure; Gilson, Éric

doi:10.1038/sj.onc.1209135

Cited by 24 publications

(16 citation statements)

References 55 publications

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“…Accordingly, TRF2-depleted telomeres appear deprotected or uncapped and can undergo end-to-end fusions and subsequent chromosome abnormalities (4,18,19). Along the same line, we recently showed that, in checkpoint-compromised telomerasepositive human fibroblasts, TRF2 inhibition promotes heritable changes, associated with a burst of telomere instability, that increase the ability to grow in soft agar (20). Strikingly, we also reported that the expression of a dominant-negative form of TRF2 in a melanoma cell line markedly inhibits its tumorigenic ability (21), suggesting that TRF2 inhibition can also counteract some of the steps involved in tumorigenesis.…”

Section: Introductionmentioning

confidence: 63%

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Telomere damage induced by the G-quadruplex ligand RHPS4 has an antitumor effect

Salvati¹,

Leonetti²,

et al. 2007

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Functional telomeres are required for the replicability of cancer cells. The G-rich strand of telomeric DNA can fold into a 4-stranded structure known as the G-quadruplex (G4), whose stabilization alters telomere function limiting cancer cell growth. Therefore, the G4 ligand RHPS4 may possess antitumor activity. Here, we show that RHPS4 triggers a rapid and potent DNA damage response at telomeres in human transformed fibroblasts and melanoma cells, characterized by the formation of several telomeric foci containing phosphorylated DNA damage response factors γ-H2AX, RAD17, and 53BP1. This was dependent on DNA repair enzyme ATR, correlated with delocalization of the protective telomeric DNA-binding protein POT1, and was antagonized by overexpression of POT1 or TRF2. In mice, RHPS4 exerted its antitumor effect on xenografts of human tumor cells of different histotype by telomere injury and tumor cell apoptosis. Tumor inhibition was accompanied by a strong DNA damage response, and tumors overexpressing POT1 or TRF2 were resistant to RHPS4 treatment. These data provide evidence that RHPS4 is a telomere damage inducer and that telomere disruption selectively triggered in malignant cells results in a high therapeutic index in mice. They also define a functional link between telomere damage and antitumor activity and reveal the key role of telomere-protective factors TRF2 and POT1 in response to this anti-telomere strategy.

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Section: Introductionmentioning

confidence: 63%

“…Transformed BJ fibroblasts expressing hTERT and SV40 early region (BJ-EHLT) were maintained as previously described (20). Human M14 melanoma, CG5 breast carcinoma, and HT29 colon carcinoma lines were previously described (45)(46)(47).…”

Section: Methodsmentioning

confidence: 99%

Telomere damage induced by the G-quadruplex ligand RHPS4 has an antitumor effect

Salvati¹,

Leonetti²,

et al. 2007

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“…TRF2 inhibition has been shown to promote mutations that increase the ability of immortalised cells to grow in soft agar, although the capacity of tumour growth in nude mice was not similarly increased (Brunori et al, 2006). This transforming activity was associated with a burst of telomere instability, independent of telomere length reduction.…”

Section: Is Telomere Shortening Too Fast or Telomerase Too Slow?mentioning

confidence: 85%

Telomere dysfunction and telomerase activation in cancer – a pathological paradox?

Calcagnile¹,

Gisselsson²

2007

Cytogenet Genome Res

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Telomerase is expressed in more than 90% of human cancers. Telomere maintenance by this enzyme is believed to safeguard genomic integrity in neoplastic cells. Nevertheless, many telomerase-expressing tumours exhibit chromosomal instability triggered by short, dysfunctional telomeres, implying that active telomerase is not sufficient for preserving a functional telosomic nucleoprotein complex in cancer cells. We here examine three possible solutions to this ostensible paradox. First, prior to telomerase activation, telomere erosion may have evolved to a level where telomeric repeat sequences are too short to provide a functional substrate for telomerase enzyme activity. Second, mechanisms other than the continuous telomere erosion counteracted by telomerase may contribute to rapid shortening of telomere repeats. Third, dysfunction of telomere-regulating proteins may result in direct telomere uncapping. Moreover, telomerase may contribute to tumour development also through mechanisms unrelated to telomere length maintenance. Taken together, the available data on the role of telomerase in cancer strongly support that inhibition of this enzyme is a feasible strategy for cancer therapy.

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“…Human immortilized BJ-hTERT and transformed BJ-EHLT/RasV12 fibroblasts were obtained and maintained as described (57,58). The wild-type and p53-deficient colon carcinoma HCT116 cells were obtained by Dr Vogelstein, Johns Hopkins University.…”

Section: Methodsmentioning

confidence: 99%

SIRT6 interacts with TRF2 and promotes its degradation in response to DNA damage

Rizzo¹,

Iachettini²,

Salvati³

et al. 2016

Nucleic Acids Research

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Telomere repeat binding factor 2 (TRF2) has been increasingly recognized to be involved in telomere maintenance and DNA damage response. Here, we show that TRF2 directly binds SIRT6 in a DNA independent manner and that this interaction is increased upon replication stress. Knockdown of SIRT6 up-regulates TRF2 protein levels and counteracts its down-regulation during DNA damage response, leading to cell survival. Moreover, we report that SIRT6 deactetylates in vivo the TRFH domain of TRF2, which in turn, is ubiquitylated in vivo activating the ubiquitin-dependent proteolysis. Notably, overexpression of the TRF2cT mutant failed to be stabilized by SIRT6 depletion, demonstrating that the TRFH domain is required for its post-transcriptional modification. Finally, we report an inverse correlation between SIRT6 and TRF2 protein expression levels in a cohort of colon rectal cancer patients. Taken together our findings describe TRF2 as a novel SIRT6 substrate and demonstrate that acetylation of TRF2 plays a crucial role in the regulation of TRF2 protein stability, thus providing a new route for modulating its expression level during oncogenesis and damage response.

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

Cited by 24 publications

References 55 publications

Telomere damage induced by the G-quadruplex ligand RHPS4 has an antitumor effect

Telomere damage induced by the G-quadruplex ligand RHPS4 has an antitumor effect

Telomere dysfunction and telomerase activation in cancer – a pathological paradox?

SIRT6 interacts with TRF2 and promotes its degradation in response to DNA damage

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