Salvati Erica, Rizzo Angela, Iachettini Sara, Zizza Pasquale, Cingolani Chiara, D'Angelo Carmen, Porru Manuela, Mondello Chiara, Aiello Aurora, Farsetti Antonella, Gilson Eric, Leonetti Carlo, Biroccio Annamaria
Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, Rome, Italy.
Istituto di Genetica Molecolare, National Research Council (CNR), Pavia, Italy.
Nucleic Acids Res. 2015 Feb 18;43(3):1759-69. doi: 10.1093/nar/gkv006. Epub 2015 Jan 23.
Here, with the aim of obtaining insight into the intriguing selectivity of G-quadruplex (G4) ligands toward cancer compared to normal cells, a genetically controlled system of progressive transformation in human BJ fibroblasts was analyzed. Among the different comparative evaluations, we found a progressive increase of DNA damage response (DDR) markers throughout the genome from normal toward immortalized and transformed cells. More interestingly, sensitivity to G4 ligands strongly correlated with the presence of a basal level of DNA damage, including at the telomeres, where the chromosome ends were exposed to the DDR without concurrent induction of DNA repair activity, as revealed by the lack of 53BP1 recruitment and telomere aberrations. The link between telomere uncapping and the response to G4 stabilization was directly assessed by showing that a partial TRF2 depletion, causing a basal level of telomere localized DDR, rendered telomerized fibroblasts prone to G4-induced telomere damage and anti-proliferative defects. Taken together these data strongly indicate that the presence of a basal level of telomere-associated DDR is a determinant of susceptibility to G4 stabilization.
在此，为了深入了解与正常细胞相比，G-四链体（G4）配体对癌细胞的有趣选择性，我们分析了人BJ成纤维细胞中基因控制的渐进转化系统。在不同的比较评估中，我们发现从正常细胞到永生化细胞和转化细胞，全基因组中DNA损伤反应（DDR）标记物逐渐增加。更有趣的是，对G4配体的敏感性与基础水平的DNA损伤密切相关，包括端粒处，染色体末端暴露于DDR但未同时诱导DNA修复活性，这通过缺乏53BP1募集和端粒畸变得以揭示。通过显示部分TRF2缺失导致端粒局部DDR的基础水平，使端粒化的成纤维细胞易于受到G4诱导的端粒损伤和抗增殖缺陷，直接评估了端粒解帽与对G4稳定化反应之间的联系。综合这些数据强烈表明，基础水平的端粒相关DDR的存在是对G4稳定化敏感性的决定因素。
