Targeted inhibition of Replication Protein A reveals cytotoxic activity, synergy with chemotherapeutic DNA-damaging agents, and insight into cellular function.
Targeted inhibition of Replication Protein A reveals cytotoxic activity, synergy with chemotherapeutic DNA-damaging agents, and insight into cellular function.
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DOI：
10.1158/0008-5472.can-09-3422
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发表时间：
2010-04-15
期刊：
影响因子：
11.2
通讯作者：
Turchi JJ
中科院分区：
文献类型：
--
作者：
Shuck SC;Turchi JJ
用单一药剂靶向不受控制的细胞增殖和对DNA损伤化疗药物的抗性在癌症治疗中具有显著的潜力。RPA是真核单链DNA结合蛋白，通过DNA复制和修复作用对基因组的维持和稳定至关重要。我们已经发现了一种新型小分子，它可以抑制RPA的体外和细胞ssDNA结合活性，阻止细胞周期进展，诱导细胞毒性并增加化疗DNA损伤剂的功效。这些结果为RPA-ssDNA相互作用在染色体维持和稳定中的机制提供了新的见解。这代表了第一个分子靶向真核DNA结合抑制剂，并揭示了靶向蛋白质-DNA相互作用作为癌症治疗策略的实用性。
Targeting uncontrolled cell proliferation and resistance to DNA damaging chemotherapeutics with a single agent has significant potential in cancer treatment. RPA, the eukaryotic single-strand (ss) DNA binding protein, is essential for genomic maintenance and stability via roles in both DNA replication and repair. We have identified a novel small molecule that inhibits the in vitro and cellular ssDNA binding activity of RPA, prevents cell cycle progression, induces cytotoxicity and increases the efficacy of chemotherapeutic DNA damaging agents. These results provide new insight into the mechanism of RPA–ssDNA interactions in chromosome maintenance and stability. This represents the first molecularly targeted eukaryotic DNA binding inhibitor and reveals the utility of targeting a protein-DNA interaction as a therapeutic strategy for cancer treatment.