Mammalian Telomeres End in a Large Duplex Loop

Griffith, Jack D.; Comeau, Laurey; Rosenfield, Soraya I.; Stansel, Rachel M.; Bianchi, Alessandro; Moss, Heidi; Lange, Titia de

doi:10.1016/s0092-8674(00)80760-6

Cited by 2,180 publications

(1,855 citation statements)

References 48 publications

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“…The formation of G-quadruplex structures has been proposed as the Telomestatin dissociates TRF2 from telomeres H Tahara et al molecular mechanism that affords 3 0 overhang protection (Han and Hurley, 2000). Griffith and de Lange have demonstrated using electron microscopy that TRF2 proteins can remodel telomeric DNA into large duplex loop (t-loop) in vitro (Griffith et al, 1999), and various models of t-loop formation involving G-quadruplex DNA have been proposed (Han and Hurley, 2000). For example, the 3 0 overhang can fold over to form an intramolecular G-quadruplex (Williamson et al, 1989).…”

Section: Discussionmentioning

confidence: 99%

“…Conversely, expression of a dominant-negative mutant allele of TRF2, TRF2 DBDM , in human cells results in loss of the 3 0 overhang of telomeres, chromosome end-to-end fusions, and activation of the ATM/p53 DNA damage response pathway (Karlseder et al, 1999). An electron microscopy study has shown that TRF2 itself has the ability to remodel telomeric DNA into a 't-loop' (Stansel et al, 2001), in which the single-stranded guanine-rich terminus invades the duplex region of the telomere (Griffith et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

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G-Quadruplex stabilization by telomestatin induces TRF2 protein dissociation from telomeres and anaphase bridge formation accompanied by loss of the 3′ telomeric overhang in cancer cells

et al. 2006

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Inhibition of telomerase activity by telomerase inhibitors induces a gradual loss of telomeres, and this in turn causes cancer cells to enter to a crisis stage. Here, we report the telomerase inhibitor telomestatin, which is known to stabilize G-quadruplex structures at 3 0 single-stranded telomeric overhangs (G-tails), rapidly dissociates TRF2 from telomeres in cancer cells within a week, when given at a concentration that does not cause normal cells to die. The G-tails were dramatically reduced upon short-term treatment with the drug in cancer cell lines, but not in normal fibroblasts and epithelial cells. In addition, telomestatin also induced anaphase bridge formation in cancer cell lines. These effects of telomestatin were similar to those of dominant negative TRF2, which also causes a prompt loss of the telomeric G-tails and induces an anaphase bridge. These results indicate that telomestatin exerts its anticancer effect not only through inhibiting telomere elongation, but also by rapidly disrupting the capping function at the very ends of telomeres. Unlike conventional telomerase inhibitors that require long-term treatments, the G-quadruplex stabilizer telomestatin induced prompt cell death, and it was selectively effective in cancer cells. This study also identifies the TRF2 protein as a therapeutic target for treating many types of cancer which have the TRF2 protein at caps of the telomere DNA of each chromosome.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

G-Quadruplex stabilization by telomestatin induces TRF2 protein dissociation from telomeres and anaphase bridge formation accompanied by loss of the 3′ telomeric overhang in cancer cells

et al. 2006

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“…The most terminal, single-stranded region of telomeres loop back and pair with an internal double-stranded location forming a stable loop structure -the telomeric cap (Griffith et al, 1999). Cells with telomeres in their capped state exhibit enhanced proliferative capacity, whereas the uncapped form coincides with cell cycle arrest (Blasco, 2007b).…”

Section: Msc Telomere and Telomerasementioning

confidence: 99%

Controversial issue: Is it safe to employ mesenchymal stem cells in cell-based therapies?

Lepperdinger

Brunauer

Jamnig

et al. 2008

Experimental Gerontology

117

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“…Human telomeres consist of double stranded tandem repeats of the hexanucleotide sequence TTAGGG except for the terminal 3 0 G-rich overhang (Makarov et al, 1997;Wright et al, 1997). Telomeres can fold into t-loops that may result from the invasion of the 3 0 overhang into duplex DNA (Griffith et al, 1999) or into G-quadruplex (G4) DNA, an unusual DNA conformation based on guanine quartets (Oganesian and Bryan, 2007). Mammalian telomeres are associated with telomeric proteins or shelterin, forming a complex that functions to protect the ends of DNA from degradation and fusion, thus playing an essential role in controlling genomic stability (de Lange, 2005).…”

Section: Introductionmentioning

confidence: 99%

PARP1 is activated at telomeres upon G4 stabilization: possible target for telomere-based therapy

Salvati¹,

Scarsella²,

Porru³

et al. 2010

Oncogene

108

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New anti-telomere strategies represent important goals for the development of selective cancer therapies. In this study, we reported that uncapped telomeres, resulting from pharmacological stabilization of quadruplex DNA by RHPS4 (3,11-difluoro-6,8,13-trimethyl-8H-quino [4,3,2-kl]acridinium methosulfate), trigger specific recruitment and activation of poly-adenosine diphosphate (ADP) ribose polymerase I (PARP1) at the telomeres, forming several ADP-ribose polymers that co-localize with the telomeric repeat binding factor 1 protein and are inhibited by selective PARP(s) inhibitors or PARP1-specific small interfering RNAs. The knockdown of PARP1 prevents repairing of RHPS4-induced telomere DNA breaks, leading to increases in chromosome abnormalities and eventually to the inhibition of tumor cell growth both in vitro and in xenografts. More interestingly, the integration of a TOPO1 inhibitor on the combination treatment proved to have a high therapeutic efficacy ensuing a complete regression of the tumor as well as a significant increase in overall survival and cure of mice even when treatments started at a very late stage of tumor growth. Overall, this work reveals the unexplored link between the PARP1 and G-quadruplex ligands and demonstrates the excellent efficacy of a multicomponent strategy based on the use of PARP inhibitors in telomere-based therapy.

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Mammalian Telomeres End in a Large Duplex Loop

Cited by 2,180 publications

References 48 publications

G-Quadruplex stabilization by telomestatin induces TRF2 protein dissociation from telomeres and anaphase bridge formation accompanied by loss of the 3′ telomeric overhang in cancer cells

G-Quadruplex stabilization by telomestatin induces TRF2 protein dissociation from telomeres and anaphase bridge formation accompanied by loss of the 3′ telomeric overhang in cancer cells

Controversial issue: Is it safe to employ mesenchymal stem cells in cell-based therapies?

PARP1 is activated at telomeres upon G4 stabilization: possible target for telomere-based therapy

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