CNRS-UMR, Université Paris Descartes, France.
J Biol Inorg Chem. 2010 Jun;15(5):641-54. doi: 10.1007/s00775-010-0631-4. Epub 2010 Feb 27.
Telomeres, the nucleoprotein complexes located at the ends of chromosomes, are involved in chromosome protection and genome stability. Telomeric repeat binding factor 1 (TRF1) and telomeric repeat binding factor 2 (TRF2) are the two telomeric proteins that bind to duplex telomeric DNA through interactions between their C-terminal domain and several guanines of the telomeric tract. Since the antitumour drug cisplatin binds preferentially to two adjacent guanines, we have investigated whether cisplatin adducts could affect the binding of TRF1 and TRF2 to telomeric DNA and the property of TRF2 to stimulate telomeric invasion, a process that is thought to participate in the formation of the t-loop. We show that the binding of TRF1 and TRF2 to telomeric sequences selectively modified by one GG chelate of cisplatin is markedly affected by cisplatin but that the effect is more drastic for TRF2 than for TRF1 (3-5-fold more sensitivity for TRF2 than for TRF1). We also report that platinum adducts cause a decrease in TRF2-dependent stimulation of telomeric invasion in vitro. Finally, in accordance with in vitro data, analysis of telomeric composition after cisplatin treatment reveals that 60% of TRF2 dissociate from telomeres.
端粒是位于染色体末端的核蛋白复合物，参与染色体保护和基因组稳定性。端粒重复结合因子 1（TRF1）和端粒重复结合因子 2（TRF2）是两种与端粒 DNA 结合的端粒蛋白，通过其 C 端结构域与端粒序列中的几个鸟嘌呤相互作用。由于抗肿瘤药物顺铂优先与两个相邻的鸟嘌呤结合，我们研究了顺铂加合物是否会影响 TRF1 和 TRF2 与端粒 DNA 的结合，以及 TRF2 刺激端粒入侵的特性，端粒入侵被认为参与了 t 环的形成。我们发现，顺铂一个 GG 螯合物选择性修饰的端粒序列与 TRF1 和 TRF2 的结合明显受顺铂影响，但 TRF2 的影响比 TRF1 更为明显（TRF2 比 TRF1 敏感 3-5 倍）。我们还报告说，铂加合物导致体外 TRF2 依赖性端粒入侵刺激减少。最后，与体外数据一致，顺铂处理后端粒组成的分析表明，60%的 TRF2 从端粒上解离。
