Metnase is a human SET and transposase domain protein that methylates histone H3 
and promotes DNA double-strand break repair. We now show that Metnase physically 
interacts and co-localizes with Topoisomerase IIalpha (Topo IIalpha), the key 
chromosome decatenating enzyme. Metnase promotes progression through 
decatenation and increases resistance to the Topo IIalpha inhibitors ICRF-193 
and VP-16. Purified Metnase greatly enhanced Topo IIalpha decatenation of 
kinetoplast DNA to relaxed circular forms. Nuclear extracts containing Metnase 
decatenated kDNA more rapidly than those without Metnase, and neutralizing 
anti-sera against Metnase reversed that enhancement of decatenation. Metnase 
automethylates at K485, and the presence of a methyl donor blocked the 
enhancement of Topo IIalpha decatenation by Metnase, implying an internal 
regulatory inhibition. Thus, Metnase enhances Topo IIalpha decatenation, and 
this activity is repressed by automethylation. These results suggest that cancer 
cells could subvert Metnase to mediate clinically relevant resistance to Topo 
IIalpha inhibitors.