Tankyrase 1 as a target for telomere-directed molecular cancer therapeutics
Tankyrase 1 as a target for telomere-directed molecular cancer therapeutics
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DOI：
10.1016/j.ccr.2004.11.021
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发表时间：
2005-01-01
期刊：
影响因子：
50.3
通讯作者：
Tsuruo, T
中科院分区：
文献类型：
--
作者：
Seimiya, H;Muramatsu, Y;Tsuruo, T
端粒延长由端粒酶抑制在顺式端粒蛋白TRF 1。端锚聚合酶1聚（ADP-核糖基）与TRF 1结合并将其从端粒释放，从而允许端粒酶进入端粒。在这里，我们证明了端锚聚合酶1在人类癌细胞中的抑制增强了端粒酶抑制剂引起的端粒缩短，并加速了细胞死亡。相反，无论是端锚聚合酶1上调或端粒缩短，其中每一个减少TRF 1加载在染色体末端，减弱端粒酶抑制的影响。这些结果与具有较少TRF 1的端粒增加其通过端粒酶延伸的效率的想法一致。这项研究表明，酶活性和端粒的可及性都可以成为端粒酶抑制的靶点。
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.