Radiation induced transcriptional and post-transcriptional regulation of the hsa-miR-23a ∼ 27a ∼ 24-2 cluster suppresses apoptosis by stabilizing XIAP

The non-coding transcriptome, in particular microRNAs (miRNA), influences cellular survival after irradiation. However, the underlying mechanisms of radiation-induced miRNA expression changes and consequently target expression changes are poorly understood. In this study we show that a single dose of 5 Gy gamma-radiation decreases expression of the miR-23a similar to 27a similar to 24-2 cluster in the human endothelial cell-line EA.hy926 and the mammary epithelial cell-line MCF10A. In the endothelial cells this was facilitated through transcriptional regulation by promoter methylation and also at the post-transcriptional level by reduced miRNA processing through phosphorylation of Argonaute (AGO). Furthermore, we demonstrate that all three mature cluster miRNAs reduce apoptosis by increasing expression of the common target protein XIAP. These findings link a temporal succession of transcriptional and post-transcriptional regulatory mechanisms of the miR 23a similar to 24-2 similar to 27a cluster, enabling a dynamic stress response and assuring cellular survival after radiation exposure.