Proofreading of misincorporated nucleotides in DNA transcription.
Proofreading of misincorporated nucleotides in DNA transcription.
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DNA 转录中错误掺入的核苷酸的校对。
DOI：
10.1088/1478-3975/9/3/036007
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发表时间：
2012
期刊：
影响因子：
2
通讯作者：
Voliotis M
中科院分区：
文献类型：
--
作者：
Voliotis M
DNA转录的准确性对于细胞的正常功能至关重要。虽然RNA聚合酶表现出对正确核苷酸的选择性，但需要额外的转录纠错机制来实现观察到的保真度水平。最近的实验发现揭示了转录错误校正的特定机制，涉及：（i）RNA聚合酶沿着DNA的扩散易位（回溯）和（ii）不可逆的RNA切割。这种机制通过使局部易位率偏置来实现错误掺入的核苷酸的优先切割。在这里，我们研究了错误掺入的核苷酸如何影响回溯动力学，以及这种影响如何决定转录保真度的水平。我们认为回溯作为一个扩散过程中的一个周期性的，一维的能量景观，在粗粒度的水平引起相邻的局部极小值之间的跳跃过程。我们提出了一个模型，错误掺入的核苷酸如何变形这种能量景观，从而影响跳跃率。特别是，我们表明，这个模型可以用来推导出理论上的保真度（即最小分数的错误掺入核苷酸）和实际保真度相对于这个最佳的，实现特定的组合的裂解和聚合速率。最后，我们研究了影响回溯动态的外部因素如何影响转录保真度。我们表明，生物相关的负载，类似于核小体或其他转录障碍所施加的，增加纠错。
The accuracy of DNA transcription is crucial for the proper functioning of the cell. Although RNA polymerases demonstrate selectivity for correct nucleotides, additional active mechanisms of transcriptional error correction are required to achieve observed levels of fidelity. Recent experimental findings have shed light on a particular mechanism of transcriptional error correction involving:(i) diffusive translocation of the RNA polymerase along the DNA (backtracking) and (ii) irreversible RNA cleavage. This mechanism achieves preferential cleavage of misincorporated nucleotides by biasing the local rates of translocation. Here, we study how misincorporated nucleotides affect backtracking dynamics and how this effect determines the level of transcriptional fidelity. We consider backtracking as a diffusive process in a periodic, one-dimensional energy landscape, which at a coarse-grained level gives rise to a hopping process between neighbouring local minima. We propose a model for how misincorporated nucleotides deform this energy landscape and hence affect the hopping rates. In particular, we show that this model can be used to derive both the theoretical limit on the fidelity (ie the minimum fraction of misincorporated nucleotides) and the actual fidelity relative to this optimum, achieved for specific combinations of the cleavage and polymerization rates. Finally, we study how external factors influencing backtracking dynamics affect transcriptional fidelity. We show that biologically relevant loads, similar to those exerted by nucleosomes or other transcriptional barriers, increase error correction.