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A potential chemotherapeutic strategy for the selective inhibition of promutagenic DNA synthesis by nonnatural nucleotides

机译：一种潜在的化学治疗策略，用于非自然核苷酸的促销性DNA合成的选择性抑制作用

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This manuscript reports the development of nonnatural nucleotide analogues that are pref0 erentially incorporated opposite an abasic site, a common form of DNA damage. Competition experiments confirm that all of the nonnatural nucleotides tested are poorly incorporated into unmodified DNA. However, two analogues that contain extensive pi-electron density (5-nitro-indolyl-2'deoxyriboside triphosphate (5-NITP) and 5-phenyl-indolyl-2'deoxyriboside triphosphate (5-PhITP)) are selectively inserted opposite an abasic site and can prevent the incorporation of natural dNTPs. We demonstrate that the DNA polymerase is unable to extend beyond the incorporated nonnatural nucleotide, a result that provides direct evidence for their unique chain termination capabilities. Furthermore, these nonnatural analogues are more slowly excised once inserted opposite the DNA lesion compared to natural dNTPs. The rate of excision becomes significantly faster when the nonnatural analogues are paired opposite natural templating positions, a result that provides additional evidence for their preferential insertion opposite the DNA lesion. Moreover, idle turnover measurements confirm that the bacteriophage T4 polymerase more stably incorporates 5-NIMP and 5-PhIMP opposite damaged DNA compared to natural dNTPs. The reduced idle turnover of these analogues reflects favorable insertion kinetics coupled with reduced exonuclease-proofreading capacity. Collectively, these data demonstrate the ability to selectively inhibit translesion DNA synthesis in vitro. A novel strategy is proposed to potentially use these nucleoside analogues to enhance the chemotherapeutic effects of DNA damaging agents as well as a possible chemopreventive strategy to inhibit promutagenic DNA replication.
机译：该稿件报告了非自然核苷酸类似物的发展，其是前呈脱脂位点的前源掺入，一种常见的DNA损伤形式。竞争实验证实，所测试的所有非自然核苷酸都掺入未修饰的DNA中。然而，含有广泛的PI-电子密度（5-硝基 - Indolyl-2'deoxyside三磷酸（5-NITP）和5-苯基 - Indolyl-2'deoxysyiboside的两种类似物选择性地插入嘶嘶声中网站并可以防止加入自然DNTPS。我们证明DNA聚合酶不能超出掺入的非自然核苷酸，这是为其独特的链终止能力提供直接证据的结果。此外，与天然DNTP相比，在与DNA病变相对的情况下，这些非自然性类似物更慢地切除。当非自然的类似物配对相对的自然模板位置时，切除率变得明显更快，这是提供其对DNA病变相对的优先插入的额外证据的结果。此外，与天然DNTP相比，怠速流转度测量确认噬菌体T4聚合酶更稳定地掺入5-nimp和5-phimp损坏的DNA。这些类似物的降低的怠速换档反映了良好的插入动力学，加上了降低的外切释放能力。总的来说，这些数据证明了能够在体外选择性地抑制转渗的DNA合成。提出了一种新的策略来潜在地利用这些核苷类似物来增强DNA损伤剂的化学治疗效果以及可能的化学预防措施来抑制促进促销DNA复制。

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