Phosphorothioate oligonucleotides, suramin and heparin inhibit DNA-dependent protein kinase activity.
Phosphorothioate oligonucleotides, suramin and heparin inhibit DNA-dependent protein kinase activity.
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DOI：
10.1038/sj.bjc.6600191
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发表时间：
2002-04-08
影响因子：
8.8
通讯作者：
Suzuki, N
中科院分区：
文献类型：
--
作者：
Hosoi, Y;Matsumoto, Y;Tomita, M;Enomoto, A;Morita, A;Sakai, K;Umeda, N;Zhao, H-J;Nakagawa, K;Ono, T;Suzuki, N
硫代磷酸寡核苷酸和苏拉明结合肝素结合蛋白，包括DNA聚合酶，并抑制其功能。在本研究中，我们报告抑制DNA依赖性蛋白激酶活性的硫代磷酸寡核苷酸，苏拉明和肝素。硫代磷酸寡核苷酸对DNA依赖性蛋白激酶活性的抑制作用随着长度的增加而增加，并在36聚体处达到平台。硫代磷酸寡核苷酸的碱基组成不影响抑制作用。硫代磷酸寡脱氧胞苷36聚体的抑制效果可以是磷酸二酯寡脱氧胞苷36聚体的抑制效果的约200倍。用纯化的DNA依赖性蛋白激酶也观察到抑制作用，这表明DNA依赖性蛋白激酶和硫代磷酸寡核苷酸之间的直接相互作用。DNA依赖性蛋白激酶对双链DNA和硫代寡脱氧胞苷36聚体的结合位置不同，因为它们在DNA依赖性蛋白激酶的激活中不具有竞争性。苏拉明和肝素抑制DNA依赖性蛋白激酶活性，IC 50分别为1.7 μ M和0.27 μ g ml − 1。DNA依赖性蛋白激酶活性和DNA双链断裂修复在培养的细胞显着抑制苏拉明在体内的治疗。我们目前的观察结果表明，苏拉明可能会导致敏感的细胞电离辐射的DNA依赖性蛋白激酶的失活和双链断裂修复的损害。英国癌症杂志（2002）86，1143 - 1149。DOI：10.1038/sj/bjc/6600191 www.example.com © 2002英国癌症研究中心
Phosphorothioate oligonucleotides and suramin bind to heparin binding proteins including DNA polymerases, and inhibit their functions. In the present study, we report inhibition of DNA-dependent protein kinase activity by phosphorothioate oligonucleotides, suramin and heparin. Inhibitory effect of phosphorothioate oligonucleotides on DNA-dependent protein kinase activity was increased with length and reached a plateau at 36-mer. The base composition of phosphorothioate oligonucleotides did not affect the inhibitory effect. The inhibitory effect by phosphorothioate oligodeoxycytidine 36-mer can be about 200-fold greater than that by the phosphodiester oligodeoxycytidine 36-mer. The inhibitory effect was also observed with purified DNA-dependent protein kinase, which suggests direct interaction between DNA-dependent protein kinase and phosphorothioate oligonucleotides. DNA-dependent protein kinase will have different binding positions for double-stranded DNA and phosphorothioate oligodeoxycytidine 36-mer because they were not competitive in DNA-dependent protein kinase activation. Suramin and heparin inhibited DNA-dependent protein kinase activity with IC50 of 1.7 μM and 0.27 μg ml−1 respectively. DNA-dependent protein kinase activities and DNA double-stranded breaks repair in cultured cells were significantly suppressed by the treatment with suramin in vivo. Our present observations suggest that suramin may possibly result in sensitisation of cells to ionising radiation by inactivation of DNA-dependent protein kinase and the impairment of double-stranded breaks repair. British Journal of Cancer (2002) 86, 1143–1149. DOI: 10.1038/sj/bjc/6600191 www.bjcancer.com © 2002 Cancer Research UK