title: The distinctive cellular responses to DNA strand breaks caused by a DNA topoisomerase I poison in conjunction with DNA replication and RNA transcription.
abstract: Camptothecin (CPT) inhibits DNA topoisomerase I (Top1) through a non-catalytic mechanism that stabilizes the Top1-DNA cleavage complex (Top1cc) and blocks the DNA re-ligation step, resulting in the accumulation in the genome of DNA single-strand breaks (SSBs), which are converted to secondary strand breaks when they collide with the DNA replication and RNA transcription machinery. DNA strand breaks mediated by replication, which have one DNA end, are distinct in repair from the DNA double-strand breaks (DSBs) that have two ends and are caused by ionizing radiation and other agents. In contrast to two-ended DSBs, such one-ended DSBs are preferentially repaired through the homologous recombination pathway. Conversely, the repair of one-ended DSBs by the non-homologous end-joining pathway is harmful for cells and leads to cell death. The choice of repair pathway has a crucial impact on cell fate and influences the efficacy of anticancer drugs such as CPT derivatives. In addition to replication-mediated one-ended DSBs, transcription also generates DNA strand breaks upon collision with the Top1cc. Some reports suggest that transcription-mediated DNA strand breaks correlate with neurodegenerative diseases. However, the details of the repair mechanisms of, and cellular responses to, transcription-mediated DNA strand breaks still remain unclear. In this review, combining our recent results and those of previous reports, we introduce and discuss the responses to CPT-induced DNA damage mediated by DNA replication and RNA transcription.
authors.affiliation: Department of Biochemistry I, Kanazawa Medical University.
authors.forename: Ryo
authors.initials: R
authors.lastname: Sakasai
authors.forename: Kuniyoshi
authors.initials: K
authors.lastname: Iwabuchi
mesh_terms: D002166:Camptothecin / Q000494:pharmacology*; D053904:DNA Breaks, Single-Stranded; D004260:DNA Repair; D004261:DNA Replication / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D006801:Humans; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D004264:DNA Topoisomerases, Type I; C528909:TOP1 protein, human; D002166:Camptothecin