Abortive activity of Topoisomerase I: a challenge for genome integrity?

Single-strand breaks (SSB) are discontinuities in one strand of the DNA double helix and are the most common type of damages that arise in cells. SSBs arise mainly from direct attack by intracellular metabolites, however, also essential nuclear processes generate SSBs as intermediates. During the catalytic cycle of DNA topoisomerase I (Top1) a SSB is generated, which is normally transient and rapidly resealed by the enzyme. However, several situations can stabilize a Top1-generated SSB, and this poses the risk of converting the SSB into a double strand break (DSB) if encountered by the replication machinery. A DSB is a more serious treat for cells as it can fuel chromosomal rearrangements and thus jeopardize genome stability and cause cells to become cancerous. In this perspective, we discuss the cellular consequences of Top1-generated damage during DNA replication with focus on the differences between endogenous Top1-generated damage and Top1 damage generated due to the use of the drug camptothecin.