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

Area of Science:

• Molecular Biology
• Genetics
• Biochemistry

Background:

• DNA topoisomerase II (Top2) creates transient DNA breaks during its function.
• Top2 poisons trap Top2-DNA complexes, exposing these breaks.
• Cells have mechanisms to manage Top2-DNA complexes and associated DNA damage.

Purpose of the Study:

• To investigate cellular mechanisms preventing DNA damage caused by Top2 poisons.
• To identify factors involved in the stability of Top2-DNA complexes.
• To understand how cells protect the genome from Top2 poison-induced DNA breaks.

Main Methods:

• Genome-wide screen in fission yeast to identify sensitivity to Top2 poisons.
• Analysis of protein degradation pathways, including SUMOylation and ubiquitination.
• Biochemical assays to assess protein-DNA interactions and SUMO chain binding.

Main Results:

• Fission yeast lacking Rrp2 (an Snf2-family DNA translocase) show hypersensitivity to Top2 poisons.
• Loss of Rrp2 leads to enhanced SUMOylation-dependent degradation of Top2.
• Rrp2 prevents excessive Top2 degradation by competing with SUMO-targeted ubiquitin ligases (STUbLs) for SUMO chain binding and displacing SUMOylated Top2 from DNA.
• The budding yeast homolog Uls1 performs a similar genome protection role.

Conclusions:

• Rrp2 acts as a key factor in preventing Top2 degradation and subsequent DNA damage induced by Top2 poisons.
• This genome protection mechanism, involving Rrp2/Uls1, is conserved across yeast species.
• Understanding this pathway has implications for cancer treatment strategies involving Top2 inhibitors.