Key decatenating enzyme that alters DNA topology by binding to two double-stranded DNA molecules, generating a double-stranded break in one of the strands, passing the intact strand through the broken strand, and religating the broken strand (PubMed:17567603, PubMed:18790802, PubMed:22013166, PubMed:22323612). May play a role in regulating the period length of ARNTL/BMAL1 transcriptional oscillation (By similarity). ATP-dependent breakage, passage and rejoining of double-stranded DNA. Binds two Mg(2+) per subunit. The magnesium ions form salt bridges with both the protein and the DNA. Can also accept other divalent metal cations, such as Mn(2+) or Ca(2+). Specifically inhibited by the intercalating agent amsacrine. Homodimer. Interacts with COPS5. Interacts with RECQL5; this stimulates DNA decatenation. Interacts with SETMAR; stimulates the topoisomerase activity (PubMed:18790802, PubMed:20457750). Interacts with DHX9; this interaction occurs in a E2 enzyme UBE2I- and RNA-dependent manner, negatively regulates DHX9-mediated double-stranded DNA and RNA duplex helicase activity and stimulates TOP2A-mediated supercoiled DNA relaxation activity (PubMed:12711669). Interacts with HNRNPU (via C-terminus); this interaction protects the topoisomerase TOP2A from degradation and positively regulates the relaxation of supercoiled DNA in a RNA-dependent manner (By similarity). Interacts with MCM3AP isoform GANP (PubMed:23652018). Interacts with ERCC6 (PubMed:26030138). Interacts with PLSCR1 (PubMed:17567603). Interacts with GCNA; this interaction allows the resolution of topoisomerase II (TOP2A) DNA-protein cross-links (By similarity). Expressed in the tonsil, spleen, lymph node, thymus, skin, pancreas, testis, colon, kidney, liver, brain and lung (PubMed:9155056). Also found in high-grade lymphomas, squamous cell lung tumors and seminomas (PubMed:9155056). The N-terminus has several structural domains; the ATPase domain (about residues 1-265), the transducer domain (about 266-428) and the toprim domain (455-572) (PubMed:25202966). Comparing different structures shows ATP hydrolysis induces domain shifts in the N-terminus that are probably part of the mechanism of DNA cleavage and rejoining (PubMed:25202966). Phosphorylation has no effect on catalytic activity. However, phosphorylation at Ser-1106 by CSNK1D/CK1 promotes DNA cleavable complex formation. Eukaryotic topoisomerase I and II can relax both negative and positive supercoils, whereas prokaryotic enzymes relax only negative supercoils. Belongs to the type II topoisomerase family.