Article
TDP2 suppresses chromosomal translocations induced by DNA topoisomerase II during gene transcription
Author/s | Gómez Herreros, Fernando
Zagnoli Vieira, Guido Ntai, Ioanna Martínez Macías, María Isabel Anderson, Rhona M. Herrero Ruíz, Andrés Caldecott, Keith W. |
Department | Universidad de Sevilla. Departamento de Genética |
Publication Date | 2017 |
Deposit Date | 2017-08-21 |
Published in |
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Abstract | DNA 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 ... DNA 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. |
Funding agencies | Ministerio de Economía y Competitividad (MINECO). España |
Project ID. | info:eu-repo/grantAgreement/MINECO/RYC-2014-16665
info:eu-repo/grantAgreement/MINECO/BFU2016-76446-P |
Citation | Gómez Herreros, F., Zagnoli Vieira, G., Ntai, I., Martínez Macías, M.I., Anderson, R.M., Herrero Ruíz, A. y Caldecott, .W. (2017). TDP2 suppresses chromosomal translocations induced by DNA topoisomerase II during gene transcription. Nature Communications, 8 (233), 1-8. |
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