Type II DNA Topoisomerases Cause Spontaneous Double-Strand Breaks in Genomic DNA

Area of Science:

• Molecular Biology
• Genetics
• Biochemistry

Background:

• Type II DNA topoisomerase (TOP2) enzymes resolve DNA topological challenges through transient double-strand breaks and re-ligation.
• TOP2 poisons, like etoposide, stabilize TOP2-DNA cleavage complexes (TOP2ccs), leading to DNA damage.
• Spontaneously arising and hormone-induced DNA double-strand breaks (DSBs) mediated by TOP2 were previously underestimated.

Purpose of the Study:

• To review the mechanisms of spontaneously arising DNA double-strand breaks (DSBs) caused by abortive TOP2 catalysis.
• To summarize the protein machinery involved in repairing stalled TOP2-DNA cleavage complexes (TOP2ccs).
• To discuss the genotoxicity of androgens and estrogens mediated by TOP2.

Main Methods:

• Literature review of studies on TOP2 function, DNA repair, and hormone genotoxicity.
• Analysis of mechanisms underlying TOP2-mediated DNA double-strand break formation and repair.
• Synthesis of current understanding of TOP2ccs, abortive catalysis, and associated repair pathways.

Main Results:

• Abortive catalysis by TOP2, particularly when inhibited by poisons or during normal cell cycling, generates significant DNA double-strand breaks (DSBs).
• TOP2-mediated DSBs are also induced by physiological levels of androgens and estrogens.
• Efficient repair of these DSBs involves nonhomologous end joining (NHEJ) factors, BRCA1, BRCA2, MRE11 nuclease, and tyrosyl-DNA phosphodiesterase 2 (TDP2).

Conclusions:

• TOP2-mediated DNA double-strand breaks (DSBs) are a common occurrence, arising from both normal cellular processes and hormonal stimulation.
• The cellular repair of TOP2-mediated DSBs is a complex process involving multiple proteins, highlighting the importance of these pathways.
• Understanding TOP2 genotoxicity and repair is crucial for comprehending genome stability and the effects of hormonal agents.