Tankyrase 1 as a target for telomere-directed molecular cancer therapeutics

Seimiya, Hiroyuki; Muramatsu, Yukiko; Ohishi, Tomokazu; Tsuruo, Takashi

doi:10.1016/j.ccr.2004.11.021

Cited by 155 publications

(158 citation statements)

References 47 publications

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“…Although TRF1 binds to all five ARC subdomains, only the ARCV domain is required for its poly(ADP-ribosyl)ation and release from the telomeres (Seimiya et al, 2004). In agreement with an involvement of Tankyrase 1 in telomere maintenance, a recent report showed that inhibition of Tankyrase 1 accentuates the ability of a telomerase inhibitor, MST-312 to induce telomere shortening (Seimiya et al, 2005), indicating that Tankyrase 1 may be a potential therapeutic target (Seimiya, 2006). Besides its telomere function, Tankyrase 1 has also been localized to the Golgi and to the mitotic spindle poles (Smith and de Lange, 1999;Chi and Lodish, 2000).…”

Section: Introductionmentioning

confidence: 72%

Targeting Tankyrase 1 as a therapeutic strategy for BRCA-associated cancer

et al. 2009

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The BRCA1 and BRCA2 proteins are involved in the maintenance of genome stability and germ-line loss-offunction mutations in either BRCA1 or BRCA2 strongly predispose carriers to cancers of the breast and other organs. It has been demonstrated previously that inhibiting elements of the cellular DNA maintenance pathways represents a novel therapeutic approach to treating tumors in these individuals. Here, we show that inhibition of the telomere-associated protein, Tankyrase 1, is also selectively lethal with BRCA deficiency. We also demonstrate that the selectivity caused by inhibition of Tankyrase 1 is associated with an exacerbation of the centrosome amplification phenotype associated with BRCA deficiency. We propose that inhibition of Tankyrase 1 could be therapeutically exploited in BRCAassociated cancers.

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Section: Introductionmentioning

confidence: 72%

Targeting Tankyrase 1 as a therapeutic strategy for BRCA-associated cancer

et al. 2009

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“…While telomestatin removes TRF2 protein from telomeres and induces telomere dysfunction, other binding proteins may also be good targets for induction of telomere dysfunction. In fact, PARP inhibitors that inhibit tankyrase 1 enhance telomere shortening by a telomerase inhibitor and hasten cell death (Seimiya et al, 2005). The combination of tankyrase and telomerase inhibitors may offer new opportunities for realizing the promise of telomerase inhibition therapy (Shay and Wright, 2005).…”

Section: Discussionmentioning

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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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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“…PARP inhibitors were shown to induce telomere shortening, but it has been difficult to ascribe this phenotype to inhibition of tankyrase1 rather than one of the other PARPs (16). Dominant negative alleles of tankyrase1 have largely failed to yield the expected telomere shortening phenotypes (15,17), although success with one allele has been reported (16). Here we address this issue further by examining the telomere dynamics of cells targeted with tankyrase1 shRNAs and through the use of a tankyrase1-resistant allele of TRF1.…”

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confidence: 98%

“…Upon overexpression of tankyrase1 in the nucleus, TRF1 is removed from telomeres and degraded by ubiquitin-mediated proteolysis (13,14). Concomitant with the loss of TRF1, such cells display a telomere elongation phenotype that requires the catalytic activity of the PARP domain of tankyrase1 (15)(16)(17)(18). TRF1 can be protected from the effect of tankyrase1 by TIN2, which forms a ternary complex with tankyrase1 and TRF1 and blocks the PARsylation of TRF1 in vitro (18).…”

mentioning

confidence: 99%

“…Several approaches have been used to provide further evidence for such a role of endogenous tankyrase1. PARP inhibitors were shown to induce telomere shortening, but it has been difficult to ascribe this phenotype to inhibition of tankyrase1 rather than one of the other PARPs (16). Dominant negative alleles of tankyrase1 have largely failed to yield the expected telomere shortening phenotypes (15,17), although success with one allele has been reported (16).…”

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confidence: 99%

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The Role of the Poly(ADP-ribose) Polymerase Tankyrase1 in Telomere Length Control by the TRF1 Component of the Shelterin Complex

Donigian¹,

Lange

2007

Journal of Biological Chemistry

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Tankyrase1 is a multifunctional poly(ADP-ribose) polymerase that can localize to telomeres through its interaction with the shelterin component TRF1. Tankyrase1 poly(ADPribosyl)ates TRF1 in vitro, and its nuclear overexpression leads to loss of TRF1 and telomere elongation, suggesting that tankyrase1 is a positive regulator of telomere length. In agreement with this proposal, we show that tankyrase1 RNA interference results in telomere shortening proportional to the level of knockdown. Furthermore, we show that a tankyrase1-resistant form of TRF1 enforced normal telomere length control, indicating that tankyrase1 is not required downstream of TRF1 in this pathway. Thus, in human cells, tankyrase1 appears to act upstream of TRF1, promoting telomere elongation through the removal of TRF1. This pathway appears absent from mouse cells. We show that murine TRF1, which lacks the canonical tankyrase1-binding site, is not a substrate for tankyrase1 poly(ADP-ribosyl)sylation in vitro. Furthermore, overexpression of tankyrase1 in mouse nuclei did not remove TRF1 from telomeres and had no detectable effect on other components of mouse shelterin. We propose that the tankyrase1-controlled telomere extension is a human-specific elaboration that allows additional control over telomere length in telomerase positive cells.Telomeres can be elongated by the telomere-specific reverse transcriptase telomerase and shortened through the effects of DNA replication and nucleolytic attack. The TTAGGG repeat array of vertebrate telomeres has a speciesspecific length setting, suggesting that these forces are balanced in the germ line. Telomere length control has been primarily studied in human tumor cells that express telomerase (reviewed in Ref. 1). Such cells often maintain the length of their telomeres within a set range. This telomere length homeostasis is achieved through a negative feedback loop involving shelterin, the telomere-specific protein complex (2). Shelterin is comprised of six proteins (TRF1, TRF2, POT1, TPP1, TIN2, and Rap1) whose abundance at chromosome ends is dictated by the length of the duplex telomeric repeat array. All shelterin components behave as negative regulators of telomere elongation by telomerase. Inhibition of TRF1, TPP1, TIN2, and POT1 results in telomere elongation, whereas overexpression of several shelterin components shortens the length of the telomeres. Telomere healing experiments demonstrated that cells have the ability to monitor and regulate telomerase at individual telomeres, and tethering of TRF1 at subtelomeric sites showed that TRF1 can modulate telomere length in cis. These findings have resulted in a model for shelterin-dependent telomere length homeostasis whereby long telomeres contain more shelterin and thus have a diminished chance of being elongated further by telomerase. A key player in this negative feedback loop is POT1, whose binding to the single-stranded telomeric DNA appears to block telomerase in vivo (3-5) and in vitro (6 -9).The length of human telomeres can be reset by mani...

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Tankyrase 1 as a target for telomere-directed molecular cancer therapeutics

Cited by 155 publications

References 47 publications

Targeting Tankyrase 1 as a therapeutic strategy for BRCA-associated cancer

Targeting Tankyrase 1 as a therapeutic strategy for BRCA-associated cancer

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

The Role of the Poly(ADP-ribose) Polymerase Tankyrase1 in Telomere Length Control by the TRF1 Component of the Shelterin Complex

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