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Title: TDP2 suppresses chromosomal translocations induced by DNA topoisomerase II during gene transcription.
Authors: Gómez-Herreros, Fernando
Zagnoli-Vieira, Guido
Ntai, Ioanna
Martínez-Macías, María Isabel
Anderson, Rhona M
Herrero-Ruíz, Andrés
Caldecott, Keith W
metadata.dc.subject.mesh: DNA Breaks, Double-Stranded
DNA End-Joining Repair
DNA Repair
DNA Topoisomerases, Type II
DNA-Binding Proteins
Nuclear Proteins
Phosphoric Diester Hydrolases
Poly-ADP-Ribose Binding Proteins
Transcription Factors
Transcription, Genetic
Translocation, Genetic
Issue Date: 10-Aug-2017
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 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.
metadata.dc.identifier.doi: 10.1038/s41467-017-00307-y
Appears in Collections:Producción 2020

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