DNA循环为噬菌体λ开关提供稳定性和鲁棒性
DNA looping provides stability and robustness to the bacteriophage lambda switch
摘要：
λ噬菌体中控制从溶原性到溶解的过渡的λ基因调控开关对定量建模提出了独特的挑战。尽管对这种调控网络进行了广泛的表征，但溶原状态的极端稳定性的起源仍然不清楚。我们已经建立了一个随机模型，这种开关。使用前向通量采样模拟，我们表明，该模型预测一个非常低的率自发原噬菌体诱导recA突变体，与实验观察一致。在我们的模型中，由与O_L和O_R操纵子区结合的CI的八聚化形成的DNA环对于稳定性至关重要，即使当总CI的大部分被非特异性结合到基因组DNA而耗尽时，也允许溶原状态保持稳定。DNA成环还确保开关对O_R结合位点顺序的突变具有鲁棒性。我们的研究结果表明，DNA成环可以提供一种机制，以保持一个稳定的溶原状态，在面对一系列的挑战，包括嘈杂的基因表达，非特异性DNA结合和操作位点突变。
英文摘要：
The bistable gene regulatory switch controlling the transition from lysogeny to lysis in bacteriophage lambda presents a unique challenge to quantitative modeling. Despite extensive characterization of this regulatory network, the origin of the extreme stability of the lysogenic state remains unclear. We have constructed a stochastic model for this switch. Using Forward Flux Sampling simulations, we show that this model predicts an extremely low rate of spontaneous prophage induction in a recA mutant, in agreement with experimental observations. In our model, the DNA loop formed by octamerization of CI bound to the O_L and O_R operator regions is crucial for stability, allowing the lysogenic state to remain stable even when a large fraction of the total CI is depleted by nonspecific binding to genomic DNA. DNA looping also ensures that the switch is robust to mutations in the order of the O_R binding sites. Our results suggest that DNA looping can provide a mechanism to maintain a stable lysogenic state in the face of a range of challenges including noisy gene expression, nonspecific DNA binding and operator site mutations.
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