DNA topological regulation by topoisomerase IIß-DNA-PK interaction is important for controlled hypoxia-inducible gene expression [RNA-Seq]

Hypoxic stress responses are crucial for cellular and organismal survival and provoke gene regulation in diverse biological pathways including cell cycle progression and energy metabolism. Here, we identified that topoisomerase IIß (TOP2B) regulates DNA topology and transcription in hypoxiainducible genes (HIGs) in a DNA-PK-dependent manner. Cellular, mutational, and genomic analyses showed antagonistic relation between TOP2B and DNA-PK. TOP2B associates with HIGs and represses transcription by suppressing negative supercoiling formation under normoxic conditions.Under hypoxia, TOP2B is released, whereas DNA-PK and HIF1a are recruited to and activate HIGs. Overall design: Transcriptomic profiling analysis of WT and DNA-PK KO cells with or without CoCl2-induced hypoxic stress (200 µM CoCl2 supplemented for 12 h)