Smurf2-Mediated Stabilization of DNA Topoisomerase IIα Controls Genomic Integrity

• Published in: Cancer research (Chicago, Ill.) Vol. 77; no. 16; pp. 4217 - 4227
• Main Authors: Emanuelli, Andrea, Borroni, Aurora P, Apel-Sarid, Liat, Shah, Pooja A, Ayyathan, Dhanoop Manikoth, Koganti, Praveen, Levy-Cohen, Gal, Blank, Michael
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research, Inc 15.08.2017
• Subjects: Animals; Antigens, Neoplasm - genetics; Antigens, Neoplasm - metabolism; Antineoplastic drugs; Antitumor agents; Cancer; Cell Line, Tumor; Chromatin; Chromosomes; Deoxyribonucleic acid; DNA; DNA topoisomerase; DNA topoisomerase (ATP-hydrolysing); DNA Topoisomerases, Type II - genetics; DNA Topoisomerases, Type II - metabolism; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Etoposide; Etoposide - pharmacology; Genomic Instability; Heredity; Humans; Interphase - physiology; Mice; Mice, Knockout; Mitosis; Neoplasms - genetics; Neoplasms - metabolism; Proteasomes; Tissues; Ubiquitin; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-16-2828

DNA topoisomerase IIα (Topo IIα) ensures genomic integrity and unaltered chromosome inheritance and serves as a major target of several anticancer drugs. Topo IIα 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 IIα levels. Smurf2 physically interacted with Topo IIα and modified its ubiquitination status to protect Topo IIα 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 IIα-deficient cells and a hallmark of chromosome instability. Introducing Topo IIα into Smurf2-depleted cells rescued this phenomenon. Smurf2 was a determinant of Topo IIα 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 IIα, providing novel insights into its control and into the suggested tumor-suppressor functions of Smurf2. .