Single-strand nick model of DNA topoisomerase II-mediated damage in genesis of MLL translocations in infant leukemia.

DNA damage results when natural compound with properties of a DNA topoisomerase II poison induces DNA topoisomerase II-mediated single strand nicks on opposite DNA strands in MLL as well as in its partner gene and disrupts the cleavage-religation equilibrium. This creates long overhangs that serve as templates for polymerization, which results in sequence duplication. MLL and its partner gene contain a few bases of homology immediately at their points of fusion that enable DNA repair by non-homologous end joining. The schematic shows formation of the der(11) genomic breakpoint junction by attempted repair of DNA topoisomerase II-mediated damage. Similar events ensue in the creation of the genomic breakpoint junction on the other derivative chromosome.

Abbreviations: NHEJ, non-homologous end joining