RNF168 and USP10 regulate topoisomerase IIα function via opposing effects on its ubiquitylation.
Nat Commun
; 7: 12638, 2016 08 25.
Article
in En
| MEDLINE
| ID: mdl-27558965
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
DNA Topoisomerases, Type II
/
Ubiquitin Thiolesterase
/
Ubiquitin-Protein Ligases
/
Poly-ADP-Ribose Binding Proteins
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Nat Commun
Journal subject:
BIOLOGIA
/
CIENCIA
Year:
2016
Document type:
Article