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

Gómez-Herreros, Fernando, Zagnoli-Vieira, Guido, Ntai, Ioanna, Martínez-Macías, María Isabel, Anderson, Rhona M, Herrero-Ruíz, Andrés and Caldecott, Keith (2017) TDP2 suppresses chromosomal translocations induced by DNA topoisomerase II during gene transcription. Nature Communications, 8 (233). ISSN 2041-1723

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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 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.

Item Type: Article
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Research Centres and Groups: Genome Damage and Stability Centre
Subjects: Q Science > Q Science (General)
Depositing User: Sarah Frances
Date Deposited: 16 Aug 2017 11:25
Last Modified: 16 Aug 2017 11:34
URI: http://sro.sussex.ac.uk/id/eprint/69788

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Project NameSussex Project NumberFunderFunder Ref
Non-homologous End-Joining Protein Complexes and Genome StabilityG1305CANCER RESEARCH UKC6563/A16771