School of Mathematics, University of Bristol, University Walk, Bristol BS8 1TW, UK.
Phys Biol. 2012 Jun;9(3):036002. doi: 10.1088/1478-3975/9/3/036002. Epub 2012 May 3.
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 (i.e. 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.
DNA 转录的准确性对细胞的正常功能至关重要。尽管 RNA 聚合酶对正确的核苷酸具有选择性，但还需要额外的转录错误校正主动机制来实现观察到的保真度水平。最近的实验结果揭示了一种涉及：（i）RNA 聚合酶沿着 DNA 的扩散易位（回溯）和（ii）不可逆的 RNA 切割的转录错误校正特定机制。该机制通过偏置局部易位速率来优先切割错配的核苷酸。在这里，我们研究了错配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水平。我们将回溯视为周期性一维能量景观中的扩散过程，在粗粒度水平上，这导致了相邻局部最小值之间的跳跃过程。我们提出了一个模型，说明错配核苷酸如何使这个能量景观变形，从而影响跳跃速率。特别是，我们表明，该模型可以用于推导出保真度的理论极限（即错配核苷酸的最小分数）以及相对于该最优值的实际保真度，这是针对特定的切割和聚合速率组合实现的。最后，我们研究了影响回溯动力学的外部因素如何影响转录保真度。我们表明，与核小体或其他转录障碍施加的生物相关负载相似的负载会增加错误校正。
