Smurf2-Mediated Stabilization Of Dna Topoisomerase Ii Alpha Controls Genomic Integrity

DNA topoisomerase II alpha (Topo II alpha) ensures genomic integrity and unaltered chromosome inheritance and serves as a major target of several anticancer drugs. Topo II alpha function is well understood, but how its expression is regulated remains unclear. Here, we identify the E3 ubiquitin ligase Smurf2 as a physiologic regulator of Topo II alpha levels. Smurf2 physically interacted with Topo II alpha and modified its ubiquitination status to protect Topo II alpha from the proteasomal degradation in dose-and catalytically dependent manners. Smurf2-depleted cells exhibited a reduced ability to resolve DNA catenanes and pathological chromatin bridges formed during mitosis, a trait of Topo II alpha-deficient cells and a hallmark of chromosome instability. Introducing Topo II alpha into Smurf2-depleted cells rescued this phenomenon. Smurf2 was a determinant of Topo II alpha protein levels in normal and cancer cells and tissues, and its levels affected cell sensitivity to the Topo II-targeting drug etoposide. Our results identified Smurf2 as an essential regulator of Topo II alpha, providing novel insights into its control and into the suggested tumor-suppressor functions of Smurf2. (C) 2017 AACR.