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首页> 外文期刊>Chemistry: A European journal >Thermodynamics of translesion synthesis across a major DNA adduct of antitumor oxaliplatin: Differential scanning calorimetric study
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Thermodynamics of translesion synthesis across a major DNA adduct of antitumor oxaliplatin: Differential scanning calorimetric study

机译：抗肿瘤奥沙利铂主要DNA加合物跨病变合成的热力学：差示扫描量热研究

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Differential scanning calorimetry (DSC) was used to measure the thermodynamic changes associated with translesion synthesis across major lesion induced in DNA by antitumor oxaliplatin [1,2-d(GG) intrastrand cross-link]. Insertion of matched nucleotides dC at the primer terminus (across unique 3′- or 5′-dG in the unplatinated template) and subsequent extensions resulted in an incremental increase in thermodynamic parameters. In contrast, incorporation of dC opposite either platinated dG in the intrastrand cross-link formed in the template strand and subsequent extensions by one nucleotide resulted only in little changes in thermodynamics. A similar thermodynamic delay was observed for a control template primer containing a dG:dT mismatch across 3′- or 5′-dG in the template and subsequent Watson-Crick primer extensions. The thermodynamic scarcity generated by either the lesion or mismatches was not localized but extended to the 5′-downstream sites, which may be connected with the phenomenon termed "short-term memory" of replication errors retained by some DNA polymerases responding to DNA damages or mismatches. Interestingly, formation of the 1,2-d(GG) intrastrand cross-link of oxaliplatin altered the overall DSC profiles of the dG:dT mismatch template/primers only in a very small extent. While addition of matched nucleotide dC across either dG in the template strand was thermodynamically favored over the presence of a mismatched dT (ΔΔG ~0 _(310) was 7.6 or 6.8 kJ mol ~(-1), ΔΔH was 14 or 49 kJ mol ~(-1)), no such thermodynamic advantage was observed with the 1,2-d(GG) intrastrand cross-link of oxaliplatin at these positions (ΔΔG ~0 _(310) was 2.8 or -0.3 kJ mol ~(-1), ΔΔH was 4 or 9 kJ mol ~(-1)). The equilibrium thermodynamic data also provide insight into the processes associated with misincorporation of incorrect nucleotides during replication bypass across major cross-links of antitumor oxaliplatin. On the other hand, besides thermodynamic effects also kinetic factors play an important role in the processing of the cross-links of antitumor platinum drugs. The impact of the two effects in overall processing DNA adducts by a particular DNA polymerase will depend on its nature.
机译：使用差示扫描量热法（DSC）来测量与抗肿瘤奥沙利铂[1,2-d（GG）链内交联]诱导的跨主要病变的跨病变合成相关的热力学变化。匹配的核苷酸dC在引物末端插入（在未镀模板中穿过独特的3'-或5'-dG）和随后的延伸导致热力学参数的增加。相反，在模板链中形成的链内交联中，与任一镀铂的dG相对的dC的掺入以及随后一个核苷酸的延伸仅导致热力学的微小变化。对于在模板中的3'-或5'-dG上含有dG：dT错配的对照模板引物以及随后的Watson-Crick引物延伸，观察到相似的热力学延迟。由病变或错配引起的热力学缺乏不是局部的，而是延伸到5'-下游位点，这可能与某些对DNA损伤或DNA损伤的DNA聚合酶保留的复制错误的“短期记忆”现象有关。不匹配。有趣的是，奥沙利铂的1,2-d（GG）链内交联的形成仅在很小的程度上改变了dG：dT不匹配模板/引物的整体DSC谱。尽管存在不匹配的dT（ΔΔG〜0 _（310）为7.6或6.8 kJ mol〜（-1），ΔΔH为14或49 kJ mol，但在模板链中的任一dG上都通过热力学促进了匹配核苷酸dC的添加。 〜（-1）），在这些位置的奥沙利铂的1,2-d（GG）链内交联未观察到这样的热力学优势（ΔΔG〜0 _（310）为2.8或-0.3 kJ mol〜（- 1），ΔΔH为4或9 kJ mol〜（-1））。平衡热力学数据还提供了与跨抗肿瘤奥沙利铂主要交联的复制绕过过程中与不正确核苷酸的错误掺入有关的过程的见解。另一方面，除了热力学作用外，动力学因素在抗肿瘤铂药物的交联过程中也起着重要作用。两种作用对特定DNA聚合酶对DNA加合物的整体加工的影响将取决于其性质。

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