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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
TDP2 protects transcription from abortive topoisomerase activity and is required for normal neural function
Nature Genetics, Volume 46, No. 5, Year 2014
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Description
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. © 2014 Nature America, Inc. All rights reserved.
Authors & Co-Authors
Gómez-Herreros, Fernando
United Kingdom, Brighton
Genome Damage and Stability Centre
Schuurs-Hoeijmakers, Janneke H.M.
Netherlands, Nijmegen
Radboud University Medical Center
Netherlands, Nijmegen
Donders Institute for Brain, Cognition and Behaviour
McCormack, Mark
Ireland, Dublin
Royal College of Surgeons in Ireland
Greally, Marie T.
Ireland, Dublin
Our Lady's Hospital for Sick Children
Rulten, Stuart
United Kingdom, Brighton
Genome Damage and Stability Centre
Romero-Granados, Rocío
Spain, Sevilla
Universidad de Sevilla
Counihan, Timothy J.
Ireland, Galway
University Hospital Galway
Chaila, Elijah
Ireland, Dublin
Beaumont Hospital
Conroy, Judith M.
Ireland, Dublin
University College Dublin
Ennis, Sean
Ireland, Dublin
University College Dublin
Delanty, Norman
Ireland, Dublin
Royal College of Surgeons in Ireland
Ireland, Dublin
Beaumont Hospital
Cortés-Ledesma, Felipe
Spain, Sevilla
Universidad de Sevilla
de Brouwer, Arjan P.M.
Netherlands, Nijmegen
Radboud University Medical Center
Netherlands, Nijmegen
Donders Institute for Brain, Cognition and Behaviour
Cavalleri, Gianpiero L.
Ireland, Dublin
Royal College of Surgeons in Ireland
El-Khamisy, Sherif F.
United Kingdom, Sheffield
The University of Sheffield
Egypt, 6th October
Zewail City of Science and Technology
De Vries, Bert B.A.
Netherlands, Nijmegen
Radboud University Medical Center
Netherlands, Nijmegen
Donders Institute for Brain, Cognition and Behaviour
Caldecott, Keith W.
United Kingdom, Brighton
Genome Damage and Stability Centre
Statistics
Citations: 129
Authors: 17
Affiliations: 11
Identifiers
Doi:
10.1038/ng.2929
ISSN:
10614036
e-ISSN:
15461718
Research Areas
Disability
Genetics And Genomics