Insights into the biomedical effects of carboxylated single-wall carbon nanotubes on telomerase and telomeres
Insights into the biomedical effects of carboxylated single-wall carbon nanotubes on telomerase and telomeres
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DOI：
10.1038/ncomms2091
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发表时间：
2012-09-01
影响因子：
16.6
通讯作者：
Qu, Xiaogang
中科院分区：
文献类型：
--
作者：
Chen, Yong;Qu, Konggang;Qu, Xiaogang
人类富含G和C的端粒DNA都被认为是癌症治疗的特异性药物靶点。然而，由于I基序结构的不稳定性和缺乏特异的结合剂，稳定端粒I基序是否能抑制端粒酶活性尚不清楚。单壁碳纳米管(SWNTs)已被报道为第一个选择性稳定人类端粒I基序DNA的配体。在此，我们报道了单壁碳纳米管可以通过稳定I基序结构来抑制端粒酶活性。I-基序和伴随的G-四链体的持续存在最终导致端粒去帽，取代端粒结合蛋白。功能失调的端粒触发DNA损伤反应，并诱导p16和p21蛋白上调。这是第一个单壁碳纳米管可以抑制端粒酶活性并干扰癌细胞端粒功能的例子。这些结果为理解单壁碳纳米管的生物医学效应和I基序DNA的生物学重要性提供了新的见解。
Both human telomeric G-rich and C-rich DNA have been considered as specific drug targets for cancer therapy. However, due to i-motif structure instability and lack of specific binding agents, it remains unclear whether stabilization of telomeric i-motif can inhibit telomerase activity. Single-walled carbon nanotubes (SWNTs) have been reported as the first ligand that can selectively stabilize human telomeric i-motif DNA. Here we report that SWNTs can inhibit telomerase activity through stabilization of i-motif structure. The persistence of i-motif and the concomitant G-quadruplex eventually leads to telomere uncapping and displaces telomere-binding proteins from telomere. The dysfunctional telomere triggers DNA damage response and elicits upregulation of p16 and p21 proteins. This is the first example that SWNTs can inhibit telomerase activity and interfere with the telomere functions in cancer cells. These results provide new insights into understanding the biomedical effects of SWNTs and the biological importance of i-motif DNA.