SUMO-Targeted DNA Translocase Rrp2 Protects the Genome from Top2-Induced DNA Damage

5 years ago

SUMO-Targeted DNA Translocase Rrp2 Protects the Genome from Top2-Induced DNA Damage

The action of DNA topoisomerase II (Top2) creates transient DNA breaks that are normally concealed inside Top2-DNA covalent complexes. Top2 poisons, including ubiquitously present natural compounds and clinically used anti-cancer drugs, trap Top2-DNA complexes. Here, we show that cells actively prevent Top2 degradation to avoid the exposure of concealed DNA breaks. A genome-wide screen revealed that fission yeast cells lacking Rrp2, an Snf2-family DNA translocase, are strongly sensitive to Top2 poisons. Loss of Rrp2 enhances SUMOylation-dependent ubiquitination and degradation of Top2, which in turn increases DNA damage at sites where Top2-DNA complexes are trapped. Rrp2 possesses SUMO-binding ability and prevents excessive Top2 degradation by competing against the SUMO-targeted ubiquitin ligase (STUbL) for SUMO chain binding and by displacing SUMOylated Top2 from DNA. The budding yeast homolog of Rrp2, Uls1, plays a similar role, indicating that this genome protection mechanism is widely employed, a finding with implications for cancer treatment.

Graphical abstract

Teaser

Wei et al. show that the fission yeast protein Rrp2 safeguards the genome from damage induced by chemicals poisoning DNA topoisomerase II (Top2), such as the anti-cancer drug etoposide. Rrp2 binds the SUMO-modified form of Top2 and prevents it from being ubiquitinated by the SUMO-targeted ubiquitin ligase (STUbL).

Publisher URL: www.sciencedirect.com/science

DOI: S1097276517302733