Fig. 1. Topoisomerase cleavage complexes.
Topoisomerases (abbreviated Topo in panel A) utilize a catalytic tyrosine residue for nucleophilic attack and breakage of a DNA phosphoester bond. A. The polarity depends on the Topo (only human enzymes are considered here). B. Topoisomerases I (nuclear and mitochondrial Top1) form a covalent bond with the 3′-DNA end and generate a 5′-hydroxyl-end. This cleavage intermediate allow controlled rotation of the 5′-end around the intact DNA strand (see Fig. 3B). Under normal conditions, the reaction is reversible. Religation (back arrow from B -> A) is favored over cleavage and requires the alignment of the 5′-hydroxyl-end with the phosphoester tyrosyl-DNA bond for nucleophilic attack. C. All other human Topo enzymes (Top2 and Top3) have an opposite polarity compared to Top1 (see Fig. 2). They form covalent bonds with the 5′-end of the break and generate 3′-hydroxyl ends.