双链断裂簇集：一种经济有效的DNA修复策略
Double-Strand Break Clustering: An Economical and Effective Strategy for DNA Repair
AI总结：
本研究利用Dragonfly显微镜和蒙特卡洛模型，揭示了非特异性诱导的DNA双链断裂（DSB）的时空簇集规律及53BP1的相分离作用，为DNA修复机制研究和疗法改进提供新见解。
摘要：
在哺乳动物细胞中，DNA双链断裂（DSBs）的修复中心已被识别出来。然而，以往的研究主要依赖通过切割特定DNA序列来诱导特异性DSB的方法。非特异性DSB的簇集及其时空特性，尤其是由辐射等环境胁迫诱导的DSB，目前仍不明确。本研究中，我们使用Dragonfly显微镜（蜻蜓显微镜）对细胞诱导高精度损伤，发现DSB簇集发生在DNA损伤应答（DDR）和修复的早期阶段，而非修复平台期。在DDR早期，DSB簇集到已有的53BP1病灶中。不同阶段的DSB簇集对DNA修复具有不同的意义。通过控制相邻损伤点之间的距离，我们发现当距离在0.8-1.4微米时，DSB簇集的概率保持恒定，而超过1.4微米时则不会发生簇集。在0.8微米范围内，由于53BP1的相分离效应，簇集概率显著升高。我们采用蒙特卡洛方法，建立了一个关于53BP1病灶形成、分裂和融合的动力学模型。该模型准确预测了实验结果，并进一步证明了时空因素对DSB簇集的影响。这些结果表明，与特异性诱导的DSB类似，非特异性诱导的DSB也可以发生簇集。DSB簇集的程度受时间和空间因素的共同影响，这为DSB簇集的动力学以及53BP1在DNA修复过程中的作用提供了新的见解。这些发现可以增进我们对DNA损伤应答的理解，并帮助我们改进疾病中的DNA修复疗法。
英文摘要：
In mammalian cells, repair centers for DNA double-strand breaks (DSBs) have been identified. However, previous researches predominantly rely on methods that induce specific DSBs by cutting particular DNA sequences. The clustering and its spatiotemporal properties of non-specifically DSBs, especially those induced by environmental stresses such as irradiation, remains unclear. In this study, we used Dragonfly microscopy to induce high-precision damage in cells and discovered that DSB clustering during the early stages of DNA damage response (DDR) and repair, but not during the repair plateau phase. Early in DDR, DSB clustered into existing 53BP1 foci. The DSB clustering at different stages has different implications for DNA repair. By controlling the distance between adjacent damage points, we found that the probability of DSB clustering remains constant at distances of 0.8 - 1.4 um, while clustering does not occur beyond 1.4 um. Within the 0.8 um range, the probability of clustering significantly increases due to the phase separation effect of 53BP1. Using a Monte Carlo approach, we developed a dynamic model of 53BP1 foci formation, fission, and fusion. This model accurately predicts experimental outcomes and further demonstrates the temporal and spatial influences on DSB clustering. These results showed that, similarly to specifically induced DSBs, non-specifically induced DSBs can also cluster. The extent of DSB clustering is influenced by both temporal and spatial factors, which provide new insights into the dynamics of DSB clustering and the role of 53BP1 in DNA repair processes. Such findings could enhance our understanding of DNA damage responses and help us improve DNA repair therapies in disease.
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