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Mol Cell. 2017 Jun 1;66(5):581-596.e6. doi: 10.1016/j.molcel.2017.04.017. Epub 2017 May 25.

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

Author information

1
National Institute of Biological Sciences, Beijing 102206, China.
2
National Institute of Biological Sciences, Beijing 102206, China; Collaborative Innovation Center for Cancer Medicine, National Institute of Biological Sciences, Beijing 102206, China. Electronic address: dulilin@nibs.ac.cn.

Abstract

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.

KEYWORDS:

DNA damage; DNA translocase; sumoylation; topoisomerase; ubiquitination

PMID:
28552615
DOI:
10.1016/j.molcel.2017.04.017
[Indexed for MEDLINE]
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