Figure 3. Pathways for the repair of Top2 mediated DNA damage.

Following recognition of Top2 covalent complexes (perhaps by collision with replication forks), collision with other tracking proteins, such as RNA polymerase, or other undiscovered surveillance processes, repair can be initiated by proteolysis or by nucleolytic processing. Proteolysis will not completely remove the protein, since the phosphotyrosyl linkage to DNA cannot be removed by proteases. Therefore, after proteolysis, a nucleolytic processing step is still required. As illustrated, the product of nucleolytic processing is a DNA molecule containing a double-strand break. Note that Top2 can be trapped as a single strand break, since the two subunits break DNA in an independent, but coordinated process¹⁴⁴. For simplicity, the trapped structure that is illustrated shows a double strand break. Processing of a covalent complex with a single strand break might generate either a single strand break, or a double strand break. Recent experiments have demonstrated that a Top2 enzyme that can only generate single strand breaks can confer cytotoxicity in the presence of Top2 poisons³². In the case of a double strand break, repair is carried out mainly by homologous recombination or non-homologous end-joining. Repair can also take place by error-prone single strand annealing pathways. The error prone repair of Top2 generated DNA double strand breaks can generate translocations that lead to secondary malignancies. Repair of single strand breaks arising from Top2 covalent complexes have not been carefully explored.