Elevated pausing of RNA Polymerase II underlies acquired resistance to ionizing radiation

Abstract As the mainstay modality for many malignancies, ionizing radiation (IR) induces a variety of lesions in genomic DNA, evoking a multipronged DNA damage response to interrupt many cellular processes including transcription. How the global transcription cycle is altered by IR and whether it is contributing to the development of IR-resistance remain unaddressed. Here we report a genome-wide accumulation of paused RNA Polymerase II (RNAPII) after IR exposure. This increased pausing is partially maintained in cells acquired IR-resistance, notably on genes involved in radiation response and cell cycle, often leading to their downregulation. Individual knockdown some of these genes such as TP53 and NEK7 endows IR-sensitive cells with varying degrees of resistance, highlighting a novel link between elevated RNAPII pausing and the acquisition of IR-resistance. Accordingly, tuning-down the RNAPII pausing level by inhibiting CDK7 reverses IR-resistance both in cell culture and xenograft models. Our results suggest that modulation of the transcription cycle is a promising strategy to increase IR-sensitivity and thwart resistance.