Trapped topoisomerase II initiates formation of de novo duplications via the nonhomologous end-joining pathway in yeast

Abstract

Significance Transcription and replication of DNA create topological problems that are resolved by topoisomerases. These enzymes nick DNA strands to allow strand passage and then reseal the broken DNA to restore its integrity. Topoisomerase II (Top2) nicks complementary DNA strands to create double-strand break (DSB) intermediates that can be stabilized by chemotherapeutic drugs and are toxic if not repaired. We identified a mutant form of yeast Top2 that forms stabilized cleavage intermediates in the absence of drugs. Overexpression of the mutant Top2 was associated with a unique mutation signature in which small, unique segments of DNA are duplicated. These de novo duplications required the nonhomologous end-joining pathway of DSB repair, and their Top2 dependence has clinical and evolutionary implications.