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Title

TDP2 suppresses chromosomal translocations induced by DNA topoisomerase II during gene transcription

AuthorsGómez-Herreros, Fernando ; Zagnoli-Vieira, Guido; Ntai, Ioanna; Martínez-Macías, María Isabel; Anderson, Rhona M.; Herrero-Ruiz, Andrés; Caldecott, Keith W.
Issue Date2017
PublisherNature Publishing Group
CitationNature Communications 8(1): 233 (2017)
AbstractDNA 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.
Publisher version (URL)https://doi.org/10.1038/s41467-017-00307-y
URIhttp://hdl.handle.net/10261/165680
Identifiersdoi: 10.1038/s41467-017-00307-y
e-issn: 2041-1723
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