Divergent Molecular and Cellular Responses to Low and High-Dose Ionizing Radiation

Area of Science:

• Radiation biology
• Molecular toxicology
• Systems biology

Background:

• The linear no-threshold model is widely used to assess cancer risk from ionizing radiation (IR).
• However, robust evidence for this model at low doses (≤0.1 Gy) is limited.
• Understanding dose-dependent molecular responses to IR is crucial for accurate risk assessment.

Purpose of the Study:

• To investigate the dose-dependent molecular and cellular responses to low (LD; 0.1 Gy) and high (HD; 1 Gy) doses of X-rays.
• To explore novel signaling pathways and their regulation by IR.
• To elucidate the role of reactive oxygen species (ROS) in low-dose IR response.

Main Methods:

• Temporal multi-omic systems analyses, including phosphoproteomics and nascent transcriptomics.
• Irradiation of cells with varying DNA double-strand break (DSB) repair efficiencies.
• Dose-response analysis of DNA damage and molecular signaling.

Main Results:

• DNA damage response (DDR) was dose-proportional, but other molecular and cellular responses were not.
• Novel S12-PPP1R7 phospho-signaling and dephosphorylation events regulated cell cycle checkpoints.
• Low-dose IR activated NRF2-regulated antioxidant and MAPK signaling, suggesting a role for ROS, while high-dose IR predominantly activated DDR genes.
• Chromosomal damage induction remained dose-proportional across tested doses.

Conclusions:

• Molecular and cellular responses to ionizing radiation are not always linear with dose, particularly at low doses.
• Low-dose IR may induce responses mediated by ROS and antioxidant pathways, distinct from high-dose DDR.
• Further research is needed to correlate these molecular differences with long-term cancer development risks.