Telomeric G-tail is a new target for cancer therapy

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Telomere is a special structure at the end of chromosomes. Most telomere DNA is composed of double stranded DNA, but very ends of telomere DNA have single-stranded, 3’-overhang of between 50 and 400 bases in the G-rich strand, the so-called G-tail. The G-tail length is essential for formation of t-loop and chromosome maintenance. Dominant negative telomere binding protein TRF2 induces the dissociation of TRF2 binding from telomeres and the destruction of G-tail accompanied by G-tail shortening. G-tail length reduction also observed in in vitro cellular senescence. Recently, we have developed G-tail telomere HPA, a new technique to measure telomeric G-tail (Nature Methods, 2005). This method has the advantage of being simple to perform, accurate and highly sensitive for G-tail as short as 20 nucleotides. In addition, this assay is specific and quantitative for G-tail, and can be used for large-scale screening to understanding diseases associated with ageing and telomere dysfunction. Using this assay, we have measured G-tail length in cancer and normal cells treated with telomestatin, G-quadruplex stabilizing telomerase inhibitor. Interestingly, telomestatin induced rapid cell death accompanied with G-tail reduction in cancer cells, but not in normal cells. Binding of telomere binding protein TRF2 to telomere in telomestatin treated cells was examined by telomere ChIP assay. About 90 % of TRF2 was dissociated from telomere whereas TRF1 dissociation was 10%. The rate of TRF2 dissociation from telomere was well correlated with the rate of anaphase bridge formation and G-tail reduction. These results indicated that G-tail destruction compounds should be new type of powerful anti-cancer drugs, and G-tail telomere HPA have practical benefits for screening of G-tail targeted anti-cancer drugs.