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Significance The separation of DNA strands during replication and transcription creates torsional stress (supercoiling) that requires resolution by topoisomerases. Topoisomerase 1 (Top1) removes supercoils by transiently nicking one DNA strand, which allows its rotation around the intact, complementary strand. Stabilization of the covalent Top1–DNA cleavage intermediate results in potentially toxic DNA damage during replication, making this enzyme an attractive target of chemotherapeutic drugs. We find that genetic or chemical Top1 stabilization gives rise to large deletions that require the nonhomologous end-joining pathway and most likely reflect the joining of nonadjacent ends. Furthermore, the relevant Top1-mediated damage accumulates in nondividing cells, suggesting a potential mechanism for genetic change that occurs outside the context of replication.

Deletions associated with stabilization of the Top1 cleavage complex in yeast are products of the nonhomologous end-joining pathway