DNA mismatch-specific targeting and hypersensitivity of mismatch-repair-deficient cells to bulky rhodium(III) intercalators
DNA mismatch-specific targeting and hypersensitivity of mismatch-repair-deficient cells to bulky rhodium(III) intercalators
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DOI：
10.1073/pnas.0607576103
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发表时间：
2006-10-17
影响因子：
11.1
通讯作者：
Barton, Jacqueline K.
中科院分区：
文献类型：
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作者：
Hart, Jonathan R.;Glebov, Oleg;Barton, Jacqueline K.
错配修复(MMR)是维持基因组完整性的关键，而MMR的缺陷与癌变相关。笨重的Rg嵌入物针对DNA碱基错配，具有高度的特异性。在这里，我们描述了在MMR缺陷细胞和MMR熟练的细胞中应用体积大的Rg嵌入物来抑制细胞增殖的不同。在人结肠癌细胞系和正常的小鼠成纤维细胞中都可以看到与MMR缺乏症相关的Rg络合物的优先抑制作用；细胞增殖的抑制严格依赖于细胞的MMR缺乏症。此外，我们的细胞增殖分析被发现与大块金属嵌入物的DNA错配靶向相关。它是Delta-异构体在靶向碱基错配和抑制DNA合成方面的活性。此外，Rh嵌入剂通过光激活促进错配部位的链切割，我们观察到细胞的反应随光激活而增强。因此，靶向DNA错配可能为化疗设计提供一种细胞选择性策略。
Mismatch repair (MMR) is critical to maintaining the integrity of the genome, and deficiencies in MMR are correlated with cancerous transformations. Bulky rhodium intercalators target DNA base mismatches with high specificity. Here we describe the application of bulky rhodium intercalators to inhibit cellular proliferation differentially in MMR-deficient cells compared with cells that are MMR-proficient. Preferential inhibition by the rhodium complexes associated with MMR deficiency is seen both in a human colon cancer cell line and in normal mouse fibroblast cells; the inhibition of cellular proliferation depends strictly on the MMR deficiency of the cell. Furthermore, our assay of cellular proliferation is found to correlate with DNA mismatch targeting by the bulky metallointercalators. It is the Delta-isomer that is active both in targeting base mismatches and in inhibiting DNA synthesis. Additionally, the rhodium intercalators promote strand cleavage at the mismatch site with photoactivation, and we observe that the cellular response is enhanced with photoactivation. Targeting DNA mismatches may therefore provide a cell-selective strategy for chemotherapeutic design.