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

Fernando Gómez-Herreros; Janneke H M Schuurs-Hoeijmakers; Mark McCormack; Marie T Greally; Stuart Rulten; Rocío Romero-Granados; Timothy J Counihan; Elijah Chaila; Judith Conroy; Sean Ennis; Norman Delanty; Felipe Cortés-Ledesma; Arjan P M de Brouwer; Gianpiero L Cavalleri; Sherif F El-Khamisy; Bert B A de Vries; Keith W Caldecott

doi:10.1038/ng.2929

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

Nat Genet. 2014 May;46(5):516-21. doi: 10.1038/ng.2929. Epub 2014 Mar 23.

Authors

Fernando Gómez-Herreros¹, Janneke H M Schuurs-Hoeijmakers², Mark McCormack³, Marie T Greally⁴, Stuart Rulten⁵, Rocío Romero-Granados⁶, Timothy J Counihan⁷, Elijah Chaila⁸, Judith Conroy⁹, Sean Ennis⁹, Norman Delanty¹⁰, Felipe Cortés-Ledesma⁶, Arjan P M de Brouwer¹¹, Gianpiero L Cavalleri¹², Sherif F El-Khamisy¹³, Bert B A de Vries¹¹, Keith W Caldecott⁵

Affiliations

¹ 1] Genome Damage and Stability Centre, School of Biological Sciences, University of Sussex, Sussex, UK. [2].
² 1] Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. [2] Department of Cognitive Neurosciences, Donders Institute for Brain Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands. [3].
³ 1] Molecular and Cellular Therapeutics, The Royal College of Surgeons in Ireland, Dublin, Ireland. [2].
⁴ National Centre for Medical Genetics, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland.
⁵ Genome Damage and Stability Centre, School of Biological Sciences, University of Sussex, Sussex, UK.
⁶ Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Departamento de Genética, CSIC (Centro Superior de Investigaciones Científicas)-Universidad de Sevilla, Sevilla, Spain.
⁷ Department of Neurology, University Hospital Galway, Galway, Ireland.
⁸ Division of Neurology, Beaumont Hospital, Dublin, Ireland.
⁹ School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.
¹⁰ 1] Molecular and Cellular Therapeutics, The Royal College of Surgeons in Ireland, Dublin, Ireland. [2] Division of Neurology, Beaumont Hospital, Dublin, Ireland.
¹¹ 1] Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. [2] Department of Cognitive Neurosciences, Donders Institute for Brain Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands.
¹² Molecular and Cellular Therapeutics, The Royal College of Surgeons in Ireland, Dublin, Ireland.
¹³ 1] Kreb's Institute, Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield, UK. [2] Center of Genomics, Helmy Institute, Zewail City of Science and Technology, Giza, Egypt.

PMID: 24658003
DOI: 10.1038/ng.2929

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Abnormalities, Multiple / genetics*
Animals
Antigens, Neoplasm / genetics
Antigens, Neoplasm / metabolism*
Ataxia / genetics*
Base Sequence
Brain / metabolism
Chromatin Immunoprecipitation
DNA Breaks, Double-Stranded
DNA Topoisomerases, Type II / genetics
DNA Topoisomerases, Type II / metabolism*
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism*
Exome / genetics
Fluorescent Antibody Technique
Homozygote
Humans
Intellectual Disability / genetics*
Mice
Microarray Analysis
Molecular Sequence Data
Neurons / physiology
Nuclear Proteins / genetics*
Nuclear Proteins / metabolism
Phosphoric Diester Hydrolases
Poly-ADP-Ribose Binding Proteins
Real-Time Polymerase Chain Reaction
Seizures / genetics*
Sequence Analysis, DNA
Transcription Factors / genetics*
Transcription Factors / metabolism
Transcription, Genetic / genetics*

Substances

Antigens, Neoplasm
DNA-Binding Proteins
Nuclear Proteins
Poly-ADP-Ribose Binding Proteins
Transcription Factors
Phosphoric Diester Hydrolases
TDP2 protein, human
DNA Topoisomerases, Type II
TOP2A protein, human
Top2a protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding