Smurf2-mediated stabilization of DNA topoisomerase IIα controls genomic integrity

Andrea Emanuelli; Aurora P. Borroni; Liat Apel-Sarid; Pooja A. Shah; Dhanoop Manikoth Ayyathan; Praveen Koganti; Gal Levy-Cohen; Michael Blank

doi:10.1158/0008-5472.CAN-16-2828

Smurf2-mediated stabilization of DNA topoisomerase IIα controls genomic integrity

Andrea Emanuelli, Aurora P. Borroni, Liat Apel-Sarid, Pooja A. Shah, Dhanoop Manikoth Ayyathan, Praveen Koganti, Gal Levy-Cohen, Michael Blank

Bar-Ilan University - Azrieli Faculty of Medicine

Research output: Contribution to journal › Article › peer-review

24 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	4217-4227
Number of pages	11
Journal	Cancer Research
Volume	77
Issue number	16
DOIs	https://doi.org/10.1158/0008-5472.CAN-16-2828
State	Published - 15 Aug 2017

Bibliographical note

Publisher Copyright:
©2017 AACR.

Funding

This work was supported by several grants, including ICRF 00636, Marie-Curie FP-7 CIG 612816, and Dayan Family Foundation award to M. Blank. We thank Meir Shamay for helpful discussions during this article preparation and Basem Hijazi for statistical analysis. We are also grateful to Ying E. Zhang for providing Smurf2-deficient mice and for other support. This work was supported by several grants, including ICRF 00636, Marie-Curie FP-7 CIG 612816, and Dayan Family Foundation award to M. Blank. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Funders	Funder number
Dayan Family Foundation
FP7 People: Marie-Curie Actions	FP-7 CIG 612816
Marie Curie

UN SDGs

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title = "Smurf2-mediated stabilization of DNA topoisomerase IIα controls genomic integrity",

abstract = "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.",

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AU - Levy-Cohen, Gal

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Smurf2-mediated stabilization of DNA topoisomerase IIα controls genomic integrity

Abstract

Bibliographical note

Funding

UN SDGs

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