Gómez-Herreros, FernandoZagnoli-Vieira, GuidoNtai, IoannaMartínez-Macías, María IsabelAnderson, Rhona MHerrero-Ruíz, AndrésCaldecott, Keith W2023-01-252023-01-252017-08-10http://hdl.handle.net/10668/11493DNA double-strand breaks (DSBs) induced by abortive topoisomerase II (TOP2) activity are a potential source of genome instability and chromosome translocation. TOP2-induced DNA double-strand breaks are rejoined in part by tyrosyl-DNA phosphodiesterase 2 (TDP2)-dependent non-homologous end-joining (NHEJ), but whether this process suppresses or promotes TOP2-induced translocations is unclear. Here, we show that TDP2 rejoins DSBs induced during transcription-dependent TOP2 activity in breast cancer cells and at the translocation 'hotspot', MLL. Moreover, we find that TDP2 suppresses chromosome rearrangements induced by TOP2 and reduces TOP2-induced chromosome translocations that arise during gene transcription. Interestingly, however, we implicate TDP2-dependent NHEJ in the formation of a rare subclass of translocations associated previously with therapy-related leukemia and characterized by junction sequences with 4-bp of perfect homology. Collectively, these data highlight the threat posed by TOP2-induced DSBs during transcription and demonstrate the importance of TDP2-dependent non-homologous end-joining in protecting both gene transcription and genome stability.DNA double-strand breaks (DSBs) induced by topoisomerase II (TOP2) are rejoined by TDP2-dependent non-homologous end-joining (NHEJ) but whether this promotes or suppresses translocations is not clear. Here the authors show that TDP2 suppresses chromosome translocations from DSBs introduced during gene transcription.enAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/DNA Breaks, Double-StrandedDNA End-Joining RepairDNA RepairDNA Topoisomerases, Type IIDNA-Binding ProteinsHumansNuclear ProteinsPhosphoric Diester HydrolasesPoly-ADP-Ribose Binding ProteinsTranscription FactorsTranscription, GeneticTranslocation, Geneticresearch article28794467open access10.1038/s41467-017-00307-y2041-1723PMC5550487https://www.nature.com/articles/s41467-017-00307-y.pdfhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5550487/pdf