RNF168 and USP10 regulate topoisomerase II? function via opposing effects on its ubiquitylation.

ABSTRACT: Topoisomerase II? (TOP2?) 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 TOP2? and mediates its ubiquitylation. RNF168 deficiency impairs decatenation activity of TOP2? 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 TOP2? ubiquitylation and restrains its chromatin association. These findings provide a mechanistic link between the RNF168/USP10 axis and TOP2? ubiquitylation and function, and suggest a role for RNF168 in the response to anti-cancer chemotherapeutics that target TOP2.

SUBMITTER: Guturi KKN 

PROVIDER: S-EPMC5007378 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature