Alessio Olivieri, Alessandro Nicola Nardi and Marco D’Abramo*,
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引用次数: 0
Abstract
Maintaining the integrity of the genome is fundamental to living organisms. To this end, nature developed several mechanisms to find and promptly repair DNA lesions. Among them, base excision repair (BER) enzymes evolved to efficiently carry out this task. Notably, the mechanisms allowing these proteins to search for, detect, and fix DNA damage on a biologically relevant time scale still remain partially unclear. By taking MutY, a BER enzyme implied in the repair of the 8-oxoguanine–adenine mismatches, as a model system, we shed some light on the repair mechanism through a theoretical-computational approach. First, we estimated the effect of the oxidation state of the MutY iron–sulfur cluster on the protein–DNA binding. Then, the redox thermodynamics of both the protein cluster and DNA nucleobases are calculated. Finally, the charge migration kinetics along the double strand bound to the enzyme has been evaluated. The rationalization of our results indicates that the search for DNA lesions is essentially dictated by the redox chemistry of the species involved, i.e., the iron–sulfur redox cofactor and the DNA bound to the enzyme.
保持基因组的完整性是生物的根本。为此,大自然开发了多种机制来发现并及时修复 DNA 病变。其中,碱基切除修复(BER)酶就是为了高效完成这项任务而进化出来的。值得注意的是,允许这些蛋白质在生物学相关的时间尺度内搜索、检测和修复DNA损伤的机制仍然部分不清楚。MutY是一种参与修复8-氧代鸟嘌呤-腺嘌呤错配的BER酶,我们以MutY为模型系统,通过理论-计算方法揭示了修复机制。首先,我们估算了 MutY 铁硫簇的氧化态对蛋白质-DNA 结合的影响。然后,计算了蛋白质簇和 DNA 核碱基的氧化还原热力学。最后,评估了与酶结合的双链的电荷迁移动力学。我们的研究结果表明,DNA 病变的寻找基本上是由相关物种的氧化还原化学决定的,即铁硫氧化还原辅助因子和与酶结合的 DNA。
期刊介绍:
Biochemistry provides an international forum for publishing exceptional, rigorous, high-impact research across all of biological chemistry. This broad scope includes studies on the chemical, physical, mechanistic, and/or structural basis of biological or cell function, and encompasses the fields of chemical biology, synthetic biology, disease biology, cell biology, nucleic acid biology, neuroscience, structural biology, and biophysics. In addition to traditional Research Articles, Biochemistry also publishes Communications, Viewpoints, and Perspectives, as well as From the Bench articles that report new methods of particular interest to the biological chemistry community.