INSERM UMR-S 1007, Cellular Homeostasis and Cancer, 75006 Paris, France.
Paris Descartes University, Paris Sorbonne Cité, 75006 Paris, France.
Int J Mol Sci. 2018 Jul 3;19(7):1951. doi: 10.3390/ijms19071951.
It is suggested that several compounds, including G-quadruplex ligands, can target telomeres, inducing their uncapping and, ultimately, cell death. However, it has never been demonstrated whether such ligands can bind directly and quantitatively to telomeres. Here, we employed the property of platinum and platinum-G-quadruplex complexes to target G-rich sequences to investigate and quantify their covalent binding to telomeres. Using inductively coupled plasma mass spectrometry, surprisingly, we found that, in cellulo, in the presence of cisplatin, a di-functional platinum complex, telomeric DNA was platinated 13-times less than genomic DNA in cellulo, as compared to in vitro data. On the contrary, the amount of mono-functional platinum complexes (Pt-ttpy and Pt-tpy) bound either to telomeric or to genomic DNA was similar and occurred in a G-quadruplex independent-manner. Importantly, the quantification revealed that the low level of cisplatin bound to telomeric DNA could not be the direct physical cause of TRF2 displacement from telomeres. Altogether, our data suggest that platinum complexes can affect telomeres both directly and indirectly.
有人提出，包括 G-四链体配体在内的几种化合物可以靶向端粒，诱导其去帽，最终导致细胞死亡。然而，尚未证明这些配体是否可以直接和定量地与端粒结合。在这里，我们利用铂和铂-G-四链体配合物靶向富含 G 的序列的特性，研究并定量它们与端粒的共价结合。出乎意料的是，我们使用电感耦合等离子体质谱法发现，在细胞内，与体外数据相比，顺铂作为一种双功能铂配合物，在细胞内使端粒 DNA 的铂化程度比基因组 DNA 低 13 倍。相反，单功能铂配合物（Pt-ttpy 和 Pt-tpy）与端粒或基因组 DNA 的结合量相似，且以 G-四链体非依赖性方式发生。重要的是，定量结果表明，低水平的顺铂与端粒 DNA 的结合不能直接导致 TRF2 从端粒上的物理位移。总之，我们的数据表明，铂配合物可以直接和间接地影响端粒。
