Figure 3.

Cellular signaling pathways and molecules that might be involved in reprogramming mRNA translation following exposure to IR. Reactive oxygen species (ROS) and/or DNA damage produced as a result of high doses of IR are known to activate the DDR consisting of highly interconnected kinase cascades (ATM, DNA-PK, ATR). Stimulation of these pathways converges on known signaling cascades that regulate mRNA translation. The major steps of translation shown towards the bottom of the diagram in blue. Note that all 3 steps require energy in the form of GTP to nucleate the ribosome (made up of 40S and 60S ribosomal subunits) on the mRNA (initiation), to elongate the peptide chain (elongation) and to release the completed peptide (termination). Translation control is exerted largely at the initiation step and specifically by modulating the formation of the eIF4F cap-binding complex and/or activity of eIF2 through phosphorylation of its alpha subunit (eIF2α). Sequence motifs within mRNAs (shown in blue font along the mRNA and defined in the text) have different sensitivities to these control points, allowing the finely-tuned regulation of single species and/or groups of mRNAs. Radioresistant phenotypes (e.g., an enhanced DDR) could be mediated by translational reprogramming resulting from stimulation of these upstream pathways following LDR exposure.