We present a novel mathematical formalism to predict the kinetics of DNA damage repair after exposure to both low- and high-LET radiation (X rays; 350 MeV/n ⁴⁰Ar; 600 MeV/n ⁵⁶Fe). Our method is based on monitoring DNA damage repair protein 53BP1 that forms radiation-induced foci (RIF) at locations of DNA double-strand breaks (DSB) in the nucleus and comparing its expression in primary skin fibroblasts isolated from 15 mice strains. We previously reported strong evidence for clustering of nearby DSB into single repair units as opposed to the classic “contact-first” model where DSB are considered immobile. Here we apply this clustering model to evaluate the number of remaining RIF over time. We also show that the newly introduced kinetic metrics can be used as surrogate biomarkers for in vivo radiation toxicity, with potential applications in radiotherapy and human space exploration. In particular, we observed an association between the characteristic time constant of RIF repair measured in vitro and survival levels of immune cells collected from irradiated mice. Moreover, the speed of DNA damage repair correlated not only with radiation-induced cellular survival in vivo, but also with spontaneous cancer incidence data collected from the Mouse Tumor Biology database, suggesting a relationship between the efficiency of DSB repair after irradiation and cancer risk.

我们提出了一种新颖的数学形式主义，以预测暴露于低和高LET辐射（X射线； 350 MeV / n ⁴⁰ Ar； 600 MeV / n ⁵⁶ Fe）后DNA损伤修复的动力学。我们的方法基于监测DNA损伤修复蛋白53BP1的形成，该蛋白在细胞核中DNA双链断裂（DSB）的位置形成辐射诱导的病灶（RIF），并比较其在从15个小鼠品系中分离出的原代皮肤成纤维细胞中的表达。我们先前曾报道有力的证据表明，附近的DSB会聚集成单个维修单元，这与DSB被视为不可移动的经典“接触优先”模型相反。在这里，我们应用此聚类模型来评估随时间推移的剩余RIF数量。我们还表明，新引入的动力学指标可以用作替代生物标志物体内辐射毒性，在放射治疗和人类太空探索中具有潜在的应用。特别是，我们观察到在体外测得的RIF修复的特征时间常数与从辐照小鼠收集的免疫细胞的存活水平之间存在关联。此外，DNA损伤修复的速度不仅与辐射诱导的体内细胞存活率相关，而且与从Mouse Tumor Biology数据库收集的自发癌症发病率数据相关，这表明放射后DSB修复效率与癌症风险之间存在关联。