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

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

Author information

  • 11] Genome Damage and Stability Centre, School of Biological Sciences, University of Sussex, Sussex, UK. [2].
  • 21] 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].
  • 31] Molecular and Cellular Therapeutics, The Royal College of Surgeons in Ireland, Dublin, Ireland. [2].
  • 4National Centre for Medical Genetics, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland.
  • 5Genome Damage and Stability Centre, School of Biological Sciences, University of Sussex, Sussex, UK.
  • 6Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Departamento de Genética, CSIC (Centro Superior de Investigaciones Científicas)-Universidad de Sevilla, Sevilla, Spain.
  • 7Department of Neurology, University Hospital Galway, Galway, Ireland.
  • 8Division of Neurology, Beaumont Hospital, Dublin, Ireland.
  • 9School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.
  • 101] Molecular and Cellular Therapeutics, The Royal College of Surgeons in Ireland, Dublin, Ireland. [2] Division of Neurology, Beaumont Hospital, Dublin, Ireland.
  • 111] 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.
  • 12Molecular and Cellular Therapeutics, The Royal College of Surgeons in Ireland, Dublin, Ireland.
  • 131] 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.

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.

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