Rajski S R, Jackson B A, Barton J K
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Mutat Res. 2000 Jan 17;447(1):49-72. doi: 10.1016/s0027-5107(99)00195-5.
Maintaining the integrity of the genome is critical for the survival of any organism. To achieve this, many families of enzymatic repair systems which recognize and repair DNA damage have evolved. Perhaps most intriguing about the workings of these repair systems is the actual damage recognition process. What are the chemical characteristics which are common to sites of nucleic acid damage that DNA repair proteins may exploit in targeting sites? Importantly, thermodynamic and kinetic principles, as much as structural factors, make damage sites distinct from the native DNA bases, and indeed, in many cases, these are the features which are believed to be exploited by repair enzymes. Current proposals for damage recognition may not fulfill all of the demands required of enzymatic repair systems given the sheer size of many genomes, and the efficiency with which the genome is screened for damage. Here we discuss current models for how DNA damage recognition may occur and the chemical characteristics, shared by damaged DNA sites, of which repair proteins may take advantage. These include recognition based upon the thermodynamic and kinetic instabilities associated with aberrant sites. Additionally, we describe how small changes in base pair structure can alter also the unique electronic properties of the DNA base pair pi-stack. Further, we describe photophysical, electrochemical, and biochemical experiments in which mismatches and other local perturbations in structure are detected using DNA-mediated charge transport. Finally, we speculate as to how this DNA electron transfer chemistry might be exploited by repair enzymes in order to scan the genome for sites of damage.
维持基因组的完整性对于任何生物体的生存至关重要。为实现这一点，许多能够识别并修复DNA损伤的酶促修复系统家族已经进化出来。也许这些修复系统运作过程中最引人入胜的部分就是实际的损伤识别过程。DNA修复蛋白在靶向位点时可能利用的核酸损伤位点的共同化学特征是什么？重要的是，热力学和动力学原理以及结构因素，使得损伤位点与天然DNA碱基不同，实际上，在许多情况下，这些正是被认为修复酶所利用的特征。鉴于许多基因组的规模庞大，以及对基因组进行损伤筛查的效率，目前关于损伤识别的提议可能无法满足酶促修复系统的所有要求。在这里，我们讨论目前关于DNA损伤识别可能如何发生的模型，以及受损DNA位点共有的化学特征，修复蛋白可能会利用这些特征。这些包括基于与异常位点相关的热力学和动力学不稳定性的识别。此外，我们描述了碱基对结构的微小变化如何也能改变DNA碱基对π堆积的独特电子性质。此外，我们描述了光物理、电化学和生化实验，其中使用DNA介导的电荷传输来检测错配和其他局部结构扰动。最后，我们推测修复酶可能如何利用这种DNA电子转移化学来扫描基因组中的损伤位点。
