Low-dose ionizing radiation (IR) responses remain an unresolved issue in radiation biology and risk assessment. Accurate knowledge of low-dose responses is important for estimation of normal tissue risk in cancer radiotherapy or health risks from occupational or hazard exposure. Cellular responses to low-dose IR appear diverse and stochastic in nature and to date no model has been proposed to explain the underlying mechanisms. Here, we propose a hypothesis on IR-induced double-strand break (DSB)-induced cis effects (IRI-DICE) and introduce DNA sequence functionality as a submicron-scale target site with functional outcome on gene expression: DSB induction in a certain genetic target site such as promotor, regulatory element, or gene core would lead to changes in transcript expression, which may range from suppression to overexpression depending on which functional element was damaged. The DNA damage recognition and repair machinery depicts threshold behavior requiring a certain number of DSBs for induction. Stochastically distributed persistent disruption of gene expression may explain—in part—the diverse nature of low-dose responses until the repair machinery is initiated at increased absorbed dose. Radiation quality and complexity of DSB lesions are also discussed. Currently, there are no technologies available to irradiate specific genetic sites to test the IRI-DICE hypothesis directly. However, supportive evidence may be achieved by developing a computational model that combines radiation transport codes with a genomic DNA model that includes sequence functionality and transcription to simulate expression changes in an irradiated cell population. To the best of our knowledge, IRI-DICE is the first hypothesis that includes sequence functionality of different genetic elements in the radiation response and provides a model for the diversity of radiation responses in the (very) low dose regimen.

在放射生物学和风险评估中，低剂量电离辐射（IR）响应仍未解决。对低剂量反应的准确了解对于估算癌症放疗中的正常组织风险或职业或危害暴露所带来的健康风险非常重要。细胞对低剂量IR的反应在本质上似乎是多样的和随机的，迄今为止，尚未提出任何模型来解释其潜在机制。在这里，我们提出一个关于IR诱导的双链断裂（DSB）诱导的顺式效应（IRI-DICE）的假设，并介绍DNA序列功能作为亚微米级靶位点，并对基因表达产生功能性结果：在一定程度上DSB诱导遗传靶位点（如启动子，调控元件或基因核心）会导致转录本表达发生变化，根据损坏的功能元件，其范围可能从抑制到过度表达。DNA损伤识别和修复机制描述了阈值行为，需要一定数量的DSB诱导。基因表达的随机分布持续破坏可能部分解释了低剂量反应的多样性，直到修复机制以增加的吸收剂量启动。还讨论了DSB病变的辐射质量和复杂性。当前，没有可用于辐照特定遗传位点以直接测试IRI-DICE假设的技术。然而，可以通过开发将辐射运输代码与基因组DNA模型相结合的计算模型来获得支持性证据，该模型包括序列功能和转录以模拟受辐射细胞群体中的表达变化。据我们所知，IRI-DICE是第一个假说，该假说包括放射反应中不同遗传成分的序列功能，并提供了（非常）低剂量方案中放射反应多样性的模型。