Tankyrase 1 as a target for telomere-directed molecular cancer therapeutics.
Telomere elongation by telomerase is repressed in cis by the telomeric protein TRF1. Tankyrase 1 poly(ADP-ribosyl)ates TRF1 and releases it from telomeres, allowing access of telomerase to telomeres. Here we demonstrate that tankyrase 1 inhibition in human cancer cells enhances telomere shortening by a telomerase inhibitor and hastens cell death. Conversely, either tankyrase 1 upregulation or telomere shortening, each of which decreased TRF1 loading on a chromosome end, attenuated the impact of telomerase inhibition. These results are consistent with the idea that telomeres having fewer TRF1s increase the efficiency of their elongation by telomerase. This study implies that both enzyme activity and accessibility to telomeres can be targets for telomerase inhibition.
Seimiya
Hiroyuki
H
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan. hseimiya@jfcr.or.jp
Muramatsu
Yukiko
Y
Ohishi
Tomokazu
T
Tsuruo
Takashi
T
D017209:Apoptosis; D001549:Benzamides / Q000378:metabolism / Q000494:pharmacology; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D019913:Nuclear Localization Signals; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D038501:Tankyrases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016615:Telomere / Q000378:metabolism*; D035321:Telomeric Repeat Binding Protein 1 / Q000235:genetics / Q000378:metabolism
D001549:Benzamides; D004791:Enzyme Inhibitors; D019913:Nuclear Localization Signals; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D038501:Tankyrases; D019098:Telomerase; D035321:Telomeric Repeat Binding Protein 1; C470197:MST 312; C418109:TNKS protein, human