Abstract
Type II DNA topoisomerase enzymes (TOP2) catalyze topological changes by strand passage reactions. They involve passing one intact double stranded DNA duplex through a transient enzyme-bridged break in another (gated helix) followed by ligation of the break by TOP2. A TOP2 poison, etoposide blocks TOP2 catalysis at the ligation step of the enzyme-bridged break, increasing the number of stable TOP2 cleavage complexes (TOP2ccs). Remarkably, such pathological TOP2ccs are formed during the normal cell cycle as well as in postmitotic cells. Thus, this ‘abortive catalysis’ can be a major source of spontaneously arising DNA double-strand breaks (DSBs). TOP2-mediated DSBs are also formed upon stimulation with physiological concentrations of androgens and estrogens. The frequent occurrence of TOP2-mediated DSBs was previously not appreciated because they are efficiently repaired. This repair is performed in collaboration with BRCA1, BRCA2, MRE11 nuclease, and tyrosyl-DNA phosphodiesterase 2 (TDP2) with nonhomologous end joining (NHEJ) factors. This review first discusses spontaneously arising DSBs caused by the abortive catalysis of TOP2 and then summarizes proteins involved in repairing stalled TOP2ccs and discusses the genotoxicity of the sex hormones.
Highlights
Double-strand breaks (DSBs) are the most genotoxic type of DNA lesion, and a single unrepaireddouble-strand breaks (DSB) can trigger apoptosis
Recent studies have demonstrated that abortive catalysis of TOP2s poses a major threat to genome stability in addition to DSB formation caused by replication blockage (Figure 2C)
Considering a dominant role for MRE11 in the repair of stalled TOP2 cleavage complexes (TOP2ccs) [28], cells might have evolved the mechanism by which collaboration between MRE11 and nonhomologous end joining (NHEJ) performs accurate rejoining without causing deletion mutations
Summary
Double-strand breaks (DSBs) are the most genotoxic type of DNA lesion, and a single unrepaired. Lethal DSBs are generated by environmental mutagens such as ionizing-radiation and by endogenous cellular processes, with several DSBs generated per cell cycle as a consequence of replication blockage at spontaneously arising DNA lesions (Figure 1) [2,3]. They include damaged nucleotides on template strands and single-strand breaks. Homology-directed repair (HDR) proteins including BRCA1 and BRCA2 initiate strand invasion of the 30 end of nascent DNA strands into the intact sister chromatid (Step 3) followed by DNA synthesis (Step 4, green arrow) This pathway allows the fork to move past the damaged nucleotides (A) and single-strand breaks (B) (Step 5)
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