TDP2 protects transcription from abortive topoisomerase activity and is required for normal neural function

Gomez Herreros, Fernando, Schuurs-Hoeijmakers, Janneke H M, McCormack, Mark, Greally, Marie T, Rulten, Stuart, Romero-Granados, Rocio, Counihan, Timothy J, Chaila, Elijah, Conroy, Judith, Ennis, Sean, Delanty, Norman, Cortes-Ledesma, Felipe, de Brouwer, Arjan P M, Cavalleri, Gianpiero L, El-Khamisy, Sherif F, de Vries, Bert B A and Caldecott, Keith (2014) TDP2 protects transcription from abortive topoisomerase activity and is required for normal neural function. Nature Genetics, 46 (5). pp. 516-524. ISSN 1061-4036

[img] PDF - Published Version
Restricted to SRO admin only

Download (869kB) | Request a copy
[img] PDF - Accepted Version
Download (586kB)

Abstract

Topoisomerase 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.

Item Type: Article
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Subjects: Q Science > QD Chemistry > QD0241 Organic chemistry > QD0415 Biochemistry
Depositing User: Gee Wheatley
Date Deposited: 01 May 2014 10:45
Last Modified: 20 Jun 2017 05:27
URI: http://sro.sussex.ac.uk/id/eprint/48329

View download statistics for this item

📧 Request an update