ERK2-topoisomerase II regulatory axis is important for gene activation in immediate early genes

Transcription of stress-inducible genes requires synchronized and robust activation, which is critical for organismal survival and homeostasis. The function of mitogen-activated protein kinase (MAPK) signaling pathway is involved in the activation of immediate early genes (IEGs), including EGR1 and FOS , for cell growth[1][1]-[3][2]. In addition, recent studies have identified topoisomerase II (TOP2) as one of the important regulators of the transcriptional activation in IEGs[4][3]-[6][4]. However, the mechanism underlying transcriptional regulation involving TOP2 in IEG activation remains unknown. Here, we demonstrate that ERK2, but not ERK1, is important for IEG transcriptional activation and report a critical ELK1 binding sequence for ERK2 function at the EGR1 gene. Our data indicated that both ERK1 and ERK2 extensively phosphorylate the C-terminal domain of TOP2B at mutual and distinctive residues. Inhibition of ERK2 kinase activity or ERK2 knock-down interferes with transcription and deregulates TOP2B in IEGs. Furthermore, the cryo-EM structure of the TOP2B- EGR1 transcription start site-etoposide complex demonstrated breakage and dramatic bending of the double-stranded DNA, suggesting the mechanism of TOP2B-mediated transcriptional activation. Taken together, this study suggests that the activated ERK2 phosphorylates TOP2B to regulate TOP2-DNA interactions during transcriptional activation in IEGs. We propose that TOP2B association, catalysis, and dissociation on its substrate DNA are important for regulating transcription and that ERK2-mediated TOP2B phosphorylation may be important for the dissociation step. ### Competing Interest Statement The authors have declared no competing interest. [1]: #ref-1 [2]: #ref-3 [3]: #ref-4 [4]: #ref-6