title: TDP2 protects transcription from abortive topoisomerase activity and is required for normal neural function.
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.
authors.affiliation: 1] Genome Damage and Stability Centre, School of Biological Sciences, University of Sussex, Sussex, UK. [2].
authors.forename: Fernando
authors.initials: F
authors.lastname: Gómez-Herreros
authors.affiliation: 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].
authors.forename: Janneke H M
authors.initials: JH
authors.lastname: Schuurs-Hoeijmakers
authors.affiliation: 1] Molecular and Cellular Therapeutics, The Royal College of Surgeons in Ireland, Dublin, Ireland. [2].
authors.forename: Mark
authors.initials: M
authors.lastname: McCormack
authors.affiliation: National Centre for Medical Genetics, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland.
authors.forename: Marie T
authors.initials: MT
authors.lastname: Greally
authors.affiliation: Genome Damage and Stability Centre, School of Biological Sciences, University of Sussex, Sussex, UK.
authors.forename: Stuart
authors.initials: S
authors.lastname: Rulten
authors.affiliation: Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Departamento de Genética, CSIC (Centro Superior de Investigaciones Científicas)-Universidad de Sevilla, Sevilla, Spain.
authors.forename: Rocío
authors.initials: R
authors.lastname: Romero-Granados
authors.affiliation: Department of Neurology, University Hospital Galway, Galway, Ireland.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Counihan
authors.affiliation: Division of Neurology, Beaumont Hospital, Dublin, Ireland.
authors.forename: Elijah
authors.initials: E
authors.lastname: Chaila
authors.affiliation: School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.
authors.forename: Judith
authors.initials: J
authors.lastname: Conroy
authors.affiliation: School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.
authors.forename: Sean
authors.initials: S
authors.lastname: Ennis
authors.affiliation: 1] Molecular and Cellular Therapeutics, The Royal College of Surgeons in Ireland, Dublin, Ireland. [2] Division of Neurology, Beaumont Hospital, Dublin, Ireland.
authors.forename: Norman
authors.initials: N
authors.lastname: Delanty
authors.affiliation: Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Departamento de Genética, CSIC (Centro Superior de Investigaciones Científicas)-Universidad de Sevilla, Sevilla, Spain.
authors.forename: Felipe
authors.initials: F
authors.lastname: Cortés-Ledesma
authors.affiliation: 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.
authors.forename: Arjan P M
authors.initials: AP
authors.lastname: de Brouwer
authors.affiliation: Molecular and Cellular Therapeutics, The Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Gianpiero L
authors.initials: GL
authors.lastname: Cavalleri
authors.affiliation: 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.
authors.forename: Sherif F
authors.initials: SF
authors.lastname: El-Khamisy
authors.affiliation: 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.
authors.forename: Bert B A
authors.initials: BB
authors.lastname: de Vries
authors.affiliation: Genome Damage and Stability Centre, School of Biological Sciences, University of Sussex, Sussex, UK.
authors.forename: Keith W
authors.initials: KW
authors.lastname: Caldecott
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D001259:Ataxia / Q000235:genetics*; D001483:Base Sequence; D001921:Brain / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D053903:DNA Breaks, Double-Stranded; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D059472:Exome / Q000235:genetics; D005455:Fluorescent Antibody Technique; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D051379:Mice; D046228:Microarray Analysis; D008969:Molecular Sequence Data; D009474:Neurons / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases; D000075223:Poly-ADP-Ribose Binding Proteins; D060888:Real-Time Polymerase Chain Reaction; D012640:Seizures / Q000235:genetics*; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics*
chemical_list: D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D014157:Transcription Factors; D010727:Phosphoric Diester Hydrolases; C474866:TDP2 protein, human; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human; C000618812:Top2a protein, mouse