RNF168 and USP10 regulate topoisomerase IIα function via opposing effects on its ubiquitylation.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 27558965.
- Also identified by DOI 10.1038/ncomms12638 and PMC identifier 5007378.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
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.
Medical subject headings
- DNA Topoisomerases, Type II
- Poly-ADP-Ribose Binding Proteins
- Ubiquitin Thiolesterase
- Ubiquitin-Protein Ligases