化学
DNA超螺旋
DNA损伤
DNA
DNA修复
癌细胞
细胞生物学
DNA复制
癌症
遗传学
生物化学
生物
作者
Katerina Duskova,Pauline Lejault,Élie Benchimol,Régis Guillot,Sébastien Britton,Anton Granzhan,David Monchaud
摘要
Translocation of DNA and RNA polymerases along their duplex substrates results in DNA supercoiling. This torsional stress promotes the formation of plectonemic structures, including three-way DNA junction (TWJ), which can block DNA transactions and lead to DNA damage. While cells have evolved multiple mechanisms to prevent the accumulation of such structures, stabilizing TWJ through ad hoc ligands offer an opportunity to trigger DNA damage in cells with high levels of transcription and replication, such as cancer cells. Here, we develop a series of azacryptand-based TWJ ligands, we thoroughly characterize their TWJ-interacting properties in vitro and demonstrate their capacity to trigger DNA damage in rapidly dividing human cancer cells. We also demonstrate that TWJ ligands are amenable to chemically induced synthetic lethality strategies upon association with inhibitors of DNA repair, thus paving the way toward innovative drug combinations to fight cancers.
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