3 years ago

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

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

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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

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