The molecular and cellular basis of divergent dose-dependent ionising radiation response

Cancer risk from medical exposure to low dose (LD) ionizing radiation (IR) is linearly extrapolated from high dose (HD) IR without sufficient mechanistic understanding and definitive evidence. The long-term health effects of radiotherapy for cancer are unclear as secondary tumours possibly arise from the 'low-dose bath' of normal tissue,. By the age of ~45 years, most (>90%) of the survivors of paediatric cancers develop secondary tumours from cancer therapy (including radiotherapy). Here, we show that LD and HD drive molecular and cellular responses to reactive oxygen species (ROS) production and DNA damage, respectively. We found dose-proportionality only for the phosphorylation events in the DNA damage response (DDR); signalling via PPP1R7 and global (de)phosphorylation events govern the G2/M checkpoint, whereas impaired DSB repair affected the DDR signalling duration rather than amplitudes. Contrastingly, LD specifically activated NRF2-regulated antioxidant defence, redox-sensitive ERK1/2/MAPK signalling, kinome/phosphatome, mitochondrial metabolic and glycolytic pathways, whereas HD induced replication stress signalling, p53 transcription and proliferation inhibition. Dose-proportional (10-200 mGy) chromosomal damage induction suggests non(slowly) repairable DNA breaks generation without a threshold, whereas LD-specific enhanced ROS-related responses induction implies survival of cells with residual DNA damage. Overall design: Dynamic nascent BrU-RNA profiles of mouse embroyonic stem cells were generated over five different time points and three different conditions, in duplicates, using Illumina HiSeq 2500 sequencers.