RNF168 and USP10 regulate topoisomerase IIα function via opposing effects on its ubiquitylation
Research output: Contribution to journal › Article › peer-review
- Department of Medical Biophysics, Princess Margaret Cancer Centre, Ontario Cancer Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada M5G 1L7.
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.
|Early online date||25 Aug 2016|
|Publication status||E-pub ahead of print - 25 Aug 2016|