TDP2 accepted version.pdf (572.43 kB)
TDP2 protects transcription from abortive topoisomerase activity and is required for normal neural function
journal contribution
posted on 2023-06-08, 17:07 authored by Fernando Gomez Herreros, Janneke H M Schuurs-Hoeijmakers, Mark McCormack, Marie T Greally, Stuart Rulten, Rocio Romero-Granados, Timothy J Counihan, Elijah Chaila, Judith Conroy, Sean Ennis, Norman Delanty, Felipe Cortes-Ledesma, Arjan P M de Brouwer, Gianpiero L Cavalleri, Sherif F El-Khamisy, Bert B A de Vries, Keith CaldecottKeith CaldecottTopoisomerase II (TOP2) removes torsional stress from DNA and facilitates gene transcription by introducing transient DNA double-strand breaks (DSBs). Such DSBs are normally rejoined by TOP2 but on occasion can become abortive and remain unsealed. Here we identify homozygous mutations in the TDP2 gene encoding tyrosyl DNA phosphodiesterase-2, an enzyme that repairs 'abortive' TOP2-induced DSBs, in individuals with intellectual disability, seizures and ataxia. We show that cells from affected individuals are hypersensitive to TOP2-induced DSBs and that loss of TDP2 inhibits TOP2-dependent gene transcription in cultured human cells and in mouse post-mitotic neurons following abortive TOP2 activity. Notably, TDP2 is also required for normal levels of many gene transcripts in developing mouse brain, including numerous gene transcripts associated with neurological function and/or disease, and for normal interneuron density in mouse cerebellum. Collectively, these data implicate chromosome breakage by TOP2 as an endogenous threat to gene transcription and to normal neuronal development and maintenance.
History
Publication status
- Published
File Version
- Accepted version
Journal
Nature GeneticsISSN
1061-4036Publisher
Nature Publishing GroupExternal DOI
Issue
5Volume
46Page range
516-521Department affiliated with
- Sussex Centre for Genome Damage Stability Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2014-05-01First Open Access (FOA) Date
2016-04-11First Compliant Deposit (FCD) Date
2014-05-01Usage metrics
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