Reference - Detail
|Author||Wei Y, Diao LX, Lu S, Wang HT, Suo F, Dong MQ, Du LL.|
|Title||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.
|MeSH||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|
|WOS Category||BIOCHEMISTRY & MOLECULAR BIOLOGY CELL BIOLOGY|
|Yeast||FY20581 FY7884 cdc48 and top2 ts mutant S. pombe strains.|