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

Gómez-Herreros, Fernando et al.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 maintenanceThis work was funded in the Caldecott laboratory by the Medical Research Council (MRC; MR/J006750/1 and G0901606/1) and Cancer Research UK (C6563/A16771), in the Cortes-Ledesma laboratory by the Spanish government (SAF2010-21017, RYC-2009-03928 and JAE-Doc 2010-011) and European Union (PERG07-2010-268466), in the El-Khamisy laboratory by the Wellcome Trust (fellowship 085284 and grant 091043) and the Lister Institute of Preventative Medicine (fellowship), and in part by the Netherlands Organization for Health Research and Development (ZonMW; VIDI grant 917-86-319 to B.B.A.d.V.), the GENCODYS project (EU-7th-2010-241995 to B.B.A.d.V. and A.P.M.d.B.), a Brainwave–Irish Epilepsy Association/Medical Research Charities Group of Ireland/Health Research Board award (2009/001) and a Health Research Board of Ireland Translational Research Scholars award. Control samples were funded by National Institute for Mental Health (NIMH) awards (RC2MH089915, K01MH098126, R01MH099216 and R01MH097971), the Epi4K Gene Discovery in Epilepsy study (National Institute for Neurological Disorders and Stroke (NINDS) U01NS077303), the Epilepsy Genome/Phenome Project (EPGP; NINDS U01NS053998), the Center for HIV/AIDS Vaccine Immunology (CHAVI) study (National Institute of Allergy and Infectious Diseases (NIAID) UO1AIO67854), the Ellison Medical Foundation New Scholar award (AG-NS-0441-08), SAIC-Frederick, Inc. (M11-074) and Biogen Idec, Inc.Peer Reviewe

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

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