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

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posted on 2023-06-09, 07:38 authored by Fernando Gómez-Herreros, Guido Zagnoli-Vieira, Ioanna Ntai, María Isabel Martínez-Macías, Rhona M Anderson, Andrés Herrero-Ruíz, Keith CaldecottKeith Caldecott
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

Non-homologous End-Joining Protein Complexes and Genome Stability; G1305; CANCER RESEARCH UK; C6563/A16771

History

Publication status

  • Published

File Version

  • Published version

Journal

Nature Communications

ISSN

2041-1723

Publisher

Nature Publishing Group

Issue

1

Volume

8

Page range

1-9

Article number

a233

Department affiliated with

  • Sussex Centre for Genome Damage Stability Publications

Research groups affiliated with

  • Genome Damage and Stability Centre Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2017-08-16

First Open Access (FOA) Date

2017-08-16

First Compliant Deposit (FCD) Date

2017-08-16

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