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

Yi Wei; Li-Xue Diao; Shan Lu; Hai-Tao Wang; Fang Suo; Meng-Qiu Dong; Li-Lin Du

doi:10.1016/j.molcel.2017.04.017

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

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

Authors

Yi Wei¹, Li-Xue Diao¹, Shan Lu¹, Hai-Tao Wang¹, Fang Suo¹, Meng-Qiu Dong¹, Li-Lin Du²

Affiliations

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: [email protected].

PMID: 28552615
DOI: 10.1016/j.molcel.2017.04.017

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.

MeSH terms

DNA Damage* / drug effects
DNA Helicases / genetics
DNA Helicases / metabolism
DNA Topoisomerases, Type II / genetics
DNA Topoisomerases, Type II / metabolism*
DNA, Fungal / drug effects
DNA, Fungal / genetics
DNA, Fungal / metabolism*
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism*
Drug Resistance
Etoposide / pharmacology
Genome, Fungal* / drug effects
Genomic Instability* / drug effects
Mutation
Protein Binding
Protein Interaction Domains and Motifs
Proteolysis
Saccharomyces cerevisiae / enzymology
Saccharomyces cerevisiae / genetics
Saccharomyces cerevisiae Proteins / genetics
Saccharomyces cerevisiae Proteins / metabolism
Schizosaccharomyces / drug effects
Schizosaccharomyces / enzymology*
Schizosaccharomyces / genetics
Schizosaccharomyces pombe Proteins / genetics
Schizosaccharomyces pombe Proteins / metabolism*
Sumoylation*
Topoisomerase II Inhibitors / pharmacology
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism
Ubiquitination

Substances

DNA, Fungal
DNA-Binding Proteins
Rrp2 protein, S pombe
Saccharomyces cerevisiae Proteins
Schizosaccharomyces pombe Proteins
Topoisomerase II Inhibitors
Etoposide
Ubiquitin-Protein Ligases
ULS1 protein, S cerevisiae
DNA Helicases
DNA Topoisomerases, Type II