Journal Article

RNF168 and USP10 regulate topoisomerase IIα function via opposing effects on its ubiquitylation

Ng, Deborah, Kumareswaran, Ramya, Bohgaki, Miyuki, Srikumar, Tharan, Jeon, Justin, Stewart, Grant S., Bristow, Rob, Hakem, Anne, Cheung, Peter, Guturi, Kiran Kumar Naidu, Raught, Brian, Hakem, Razqallah, El Ghamrasni, Samah, Patel, Parasvi, Eldin, Mohamed Saad, Bohgaki, Toshiyuki

2016

Overview

Topoisomerase IIα (TOP2α) is essential for chromosomal condensation and segregation, as well as genomic integrity. Here we report that RNF168, an E3 ligase mutated in the human RIDDLE syndrome, interacts with TOP2α and mediates its ubiquitylation. RNF168 deficiency impairs decatenation activity of TOP2α and promotes mitotic abnormalities and defective chromosomal segregation. Our data also indicate that RNF168 deficiency, including in human breast cancer cell lines, confers resistance to the anti-cancer drug and TOP2 inhibitor etoposide. We also identify USP10 as a deubiquitylase that negatively regulates TOP2α ubiquitylation and restrains its chromatin association. These findings provide a mechanistic link between the RNF168/USP10 axis and TOP2α ubiquitylation and function, and suggest a role for RNF168 in the response to anti-cancer chemotherapeutics that target TOP2. The E3 ligase RNF168 is essential for the signalling of DNA double strand break and its mutations are associated with the RIDDLE syndrome. Here the authors identify TOP2a as substrate for RNF168 and USP10; providing a link between the RNF168/USP10 axis, TOP2a and the response to anti-cancer drugs that target TOP2.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 14/63 / 38/15 / 42/109 / 631/45/607/1159 / 692/699/67/1059/2326 / 82 / 82/58 / 96 / 96/31 / Animals / Antineoplastic Agents - pharmacology / Antineoplastic Agents - therapeutic use / Cell Line, Tumor / Chromosome Segregation - genetics / Craniofacial Abnormalities - genetics / DNA Topoisomerases, Type II - metabolism / DNA, Catenated - metabolism / Drug Resistance, Neoplasm - genetics / Etoposide - pharmacology / Etoposide - therapeutic use / Fibroblasts / Gene Knockdown Techniques / HEK293 Cells / Humanities and Social Sciences / Humans / Immunologic Deficiency Syndromes - genetics / Learning Disabilities - genetics / Mice / multidisciplinary / Mutagenesis, Site-Directed / Neoplasms - drug therapy / Neoplasms - genetics / Poly-ADP-Ribose Binding Proteins - antagonists & inhibitors / Poly-ADP-Ribose Binding Proteins - metabolism / Primary Immunodeficiency Diseases / Proteomics / RNA, Small Interfering - metabolism / Science / Science (multidisciplinary) / Topoisomerase II Inhibitors - pharmacology / Topoisomerase II Inhibitors - therapeutic use / Ubiquitin Thiolesterase - metabolism / Ubiquitin-Protein Ligases - genetics / Ubiquitin-Protein Ligases - metabolism / Ubiquitination