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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE130066 | GEO | 2022/07/01

REPOSITORIES: GEO

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Project description:DNA damage response (DDR) is a complex process, essential for cell survival. Especially deleterious type of DNA damage are DNA double-strand breaks (DSB), which can lead to genomic instability and malignant transformation if not repaired correctly. The central player in DSB detection and repair is the ATM kinase which orchestrates the action of several downstream factors. Despite substantial knowledge of DNA repair processes, still several aspects of DNA damage detection and signaling are not fully understood. Recent studies have suggested that long non-coding RNAs (lncRNAs) are involved in DDR. Here, we aimed to identify lncRNAs induced upon DNA damage in an ATM-dependent manner. 7 mRNAs and 10 lncRNAs were significantly induced 1h after ionizing radiation (IR) in healthy donors, whereas none in AT patients. 447 mRNAs and 149 lncRNAs were induced 8h after IR in the control group, while only 100 mRNAs and 3 lncRNAs in AT patients. Among IR-induced mRNAs, we found several genes with well-known functions in DDR. Gene Set Enrichment Analysis and Gene Ontology revealed delayed induction of key DDR pathways in AT patients compared to controls. The induction and dynamics of selected 9 lncRNAs were confirmed by RT-qPCR at several time-points after IR on a larger cohort. Moreover, inhibition of ATM with a specific inhibitor (KU-60019) proved that those lncRNAs are dependent on ATM. Some of the detected lncRNAs are localized next to protein-coding genes involved in DDR. We observed that induction of lncRNAs after IR preceded changes in expression of adjacent genes. This indicates that IR-induced lncRNAs may regulate the transcription of nearby genes. Subcellular fractionation into chromatin, nuclear, and cytoplasmic fractions revealed that the majority of studied lncRNAs are localized in chromatin, which further suggests their role in regulation of gene expression. In summary, our study revealed several lncRNAs induced by IR in an ATM-dependent manner. Their co-localization and co-expression with genes involved in DDR suggest that those lncRNAs may be important players in cellular response to DNA damage.

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

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