Up to 20% of solid tumors are characterized by DNA mismatch repair (MMR) deficiency and microsatellite instability that confer resistance to standard of care chemotherapy. MMR-deficient cancers have an increased mutation rate, and DNA mismatches accumulate as part of these cancers. We previously described a class of compounds, rhodium metalloinsertors, that bind DNA mismatches with high specificity and selectivity and have potential as targeted therapy. [Rh(chrysi)(phen)(PPO)]2+ (RhPPO) is the most potent, selective compound in this class and acts by targeting DNA mismatches, resulting in preferential cytotoxicity to MMR-deficient cancers. To explore further the cellular mechanism of action of RhPPO, we conjugated the metal complex to a fluorescent probe, cyanine 3 (Cy3). RhPPO-Cy3 binds DNA mismatches and retains the selectivity and potent cytotoxic activity of RhPPO for MMR-deficient cell lines. RhPPO-Cy3 forms discrete foci in the cell nucleus that overlap with sites of DNA damage, suggesting that the lesions occur at or near DNA mismatch sites. RhPPO-Cy3 foci persist over time, despite initial processing of the lesion and recruitment of repair proteins, consistent with the idea that the complex binding to a mismatch prevents repair. RhPPO-Cy3 binding does not lead to activation of p53 and the apoptotic pathway. Together, these findings support the idea that RhPPO-Cy3 binding leads to irreversible DNA damage at DNA mismatches that enables selective cytotoxicity to MMR-deficient cells.

中文翻译：

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在碱基对错配时不可逆的DNA损伤会导致荧光铑金属插入分子缀合的细胞选择性细胞毒性。

高达20％的实体瘤的特征是DNA错配修复（MMR）缺乏和微卫星不稳定性，从而赋予了对护理标准化疗的抗性。缺乏MMR的癌症的突变率增加，并且DNA错配累积成为这些癌症的一部分。先前我们描述了一类化合物，铑金属内含子，它们以高特异性和选择性结合DNA不匹配，具有作为靶向治疗的潜力。[Rh（chrysi）（phen）（PPO）] 2+（RhPPO）是此类中最有效的选择性化合物，可通过靶向DNA错配来发挥作用，从而导致对MMR缺陷型癌症的优先细胞毒性。为了进一步探索RhPPO作用的细胞机制，我们将金属络合物与荧光探针花青3（Cy3）缀合。RhPPO-Cy3结合DNA错配并保留RhPPO对MMR缺陷型细胞系的选择性和有效的细胞毒活性。RhPPO-Cy3在细胞核中形成离散的病灶，与DNA损伤的位点重叠，表明损伤发生在DNA错配位点或附近。尽管病变的初步处理和修复蛋白的募集，RhPPO-Cy3病灶仍会随着时间的推移而持续存在，这与复杂的结合错配会阻止修复的想法是一致的。RhPPO-Cy3结合不会导致p53激活和凋亡途径。总之，这些发现支持了RhPPO-Cy3结合会导致DNA错配导致不可逆的DNA损伤的想法，从而对MMR缺陷型细胞产生选择性的细胞毒性。RhPPO-Cy3在细胞核中形成离散的病灶，与DNA损伤的位点重叠，表明损伤发生在DNA错配位点或附近。尽管病变的初步处理和修复蛋白的募集，RhPPO-Cy3病灶仍会随着时间的推移而持续存在，这与复杂的结合错配会阻止修复的想法是一致的。RhPPO-Cy3结合不会导致p53激活和凋亡途径。总之，这些发现支持了RhPPO-Cy3结合会导致DNA错配导致不可逆的DNA损伤的想法，从而对MMR缺陷型细胞产生选择性的细胞毒性。RhPPO-Cy3在细胞核中形成离散的病灶，与DNA损伤的位点重叠，表明损伤发生在DNA错配位点或附近。尽管病变的初步处理和修复蛋白的募集，RhPPO-Cy3病灶仍会随着时间的推移而持续存在，这与复杂的结合错配会阻止修复的想法是一致的。RhPPO-Cy3结合不会导致p53激活和凋亡途径。总之，这些发现支持了RhPPO-Cy3结合会导致DNA错配导致不可逆的DNA损伤的想法，从而对MMR缺陷型细胞产生选择性的细胞毒性。与不匹配的复杂绑定会阻止修复的想法相一致。RhPPO-Cy3结合不会导致p53激活和凋亡途径。总之，这些发现支持了RhPPO-Cy3结合会导致DNA错配导致不可逆的DNA损伤的想法，从而使对MMR缺陷细胞的选择性细胞毒性成为可能。与不匹配的复杂绑定会阻止修复的想法相一致。RhPPO-Cy3结合不会导致p53激活和凋亡途径。总之，这些发现支持了RhPPO-Cy3结合会导致DNA错配导致不可逆的DNA损伤的想法，从而对MMR缺陷型细胞产生选择性的细胞毒性。