三维基因组中DNA双链断裂分布与辐射诱导细胞死亡之间的相关性
Correlation Between DNA Double-Strand Break Distribution in 3D Genome and Radiation-Induced Cell Death
AI总结：
该研究提出三维基因组中DSB的成簇分布决定辐射致死效应，并通过跨TAD模型与电子、碳离子径迹结构模拟验证其与剂量、LET及细胞死亡的关联。
摘要：
靶理论是解释辐射诱导细胞死亡的最经典假说，但“靶”的物理或生物学本质仍不明确。本研究假设，DNA双链断裂（DSB）在三维基因组中的分布是影响辐射诱导细胞死亡概率的关键因素。我们提出，与孤立的DSB相比，位于具有高相互作用频率的DNA片段中的成簇DSB更容易导致细胞死亡。拓扑关联结构域（TAD）可被视为评估三维基因组中DSB成簇影响的参考单位。为量化三维基因组中DSB分布与辐射诱导效应之间的这种相关性，我们开发了一个考虑DSB跨TAD分布的简化模型。利用径迹结构Monte Carlo程序模拟电子和碳离子照射，我们计算了不同辐射剂量和LET下每种情形的发生率。模拟结果表明，位于相互作用频繁的TAD中的DSB（情形3）显著比单个TAD内的成簇DSB（情形2）更可能诱导细胞死亡。此外，情形2显著比孤立DSB（情形1）更可能诱导细胞死亡。情形2和情形3的发生率随LET变化的曲线，与辐射防护中使用的辐射品质因子具有相似形状。这表明这两种情形也与高LET照射诱导的随机效应相关。我们的研究强调了三维基因组结构在放射生物学效应基本机制中的重要性。研究中的假说为调控放射生物学效应的机制提供了新视角。此外，它也为建立可预测不同剂量和LET下细胞存活的机制模型提供了有价值的参考。
英文摘要：
The target theory is the most classical hypothesis explaining radiation-induced cell death, the physical or biological nature of the "target" remains ambiguous. This study hypothesizes that the distribution of DNA double-strand breaks (DSBs) within the 3D genome is a pivotal factor affecting the probability of radiation-induced cell death. We propose that clustered DSBs in DNA segments with high interaction frequencies are more susceptible to leading to cell death than isolated DSBs. Topologically associating domains (TAD) can be regarded as the reference unit for evaluating the impact of DSB clustering in the 3D genome. To quantify this correlation between the DSB distribution in 3D genome and radiation-induced effect, we developed a simplified model considering the DSB distribution across TADs. Utilizing track-structure Monte Carlo codes to simulate the electron and carbon ion irradiation, we calculated the incidence of each case across a variety of radiation doses and LETs. Our simulation results indicate that DSBs in TADs with frequent interactions (case 3) are significantly more likely to induce cell death than clustered DSBs within a single TAD (case 2). Moreover, case 2 is significantly more likely to induce cell death than isolated DSBs (case 1). The curves of the incidence of case 2 and case 3 versus LETs have a similar shape to the radiation quality factor used in radiation protection. This indicates that these two cases are also associated with the stochastic effects induced by high LET irradiation. Our study underscores the significance of the 3D genome structure in the fundamental mechanisms of radiobiological effects. The hypothesis in our research offers novel perspectives on the mechanisms that regulate radiobiological effects. Moreover, it serves as a valuable reference for establishing mechanistic models that can predict cell survival under different doses and LETs.
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