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Research Article
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FUS (fused in sarcoma) is a component of the cellular response to topoisomerase I–induced DNA breakage and transcriptional stress

View ORCID ProfileMaria Isabel Martinez-Macias  Correspondence email, Duncan AQ Moore, Ryan L Green, View ORCID ProfileFernando Gomez-Herreros, Marcel Naumann, Andreas Hermann, Philip Van Damme, View ORCID ProfileMajid Hafezparast, View ORCID ProfileKeith W Caldecott  Correspondence email
Maria Isabel Martinez-Macias
1Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, England
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  • ORCID record for Maria Isabel Martinez-Macias
  • For correspondence: mm761@sussex.ac.uk
Duncan AQ Moore
1Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, England
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Ryan L Green
2Neuroscience, School of Life Sciences, University of Sussex, Falmer, Brighton, England
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Fernando Gomez-Herreros
1Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, England
3Instituto de Biomedicina de Sevilla, Hospital Virgen del Rocio-Centro Superior de Investigaciones Cientificas-Universidad de Sevilla, Seville, Spain
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Marcel Naumann
4Department of Neurology, Technische Universität Dresden, and German Center for Neurodegenerative Diseases (DZNE), Dresden, Germany
6Translational Neurodegeneration Section “Albrecht-Kossel”, Department of Neurology, University Medical Center Rostock, University of Rostock, Rostock, Germany
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Andreas Hermann
4Department of Neurology, Technische Universität Dresden, and German Center for Neurodegenerative Diseases (DZNE), Dresden, Germany
5Center for Transdisciplinary Neurosciences Rostock, University Medical Center Rostock, University of Rostock, Rostock, Germany
6Translational Neurodegeneration Section “Albrecht-Kossel”, Department of Neurology, University Medical Center Rostock, University of Rostock, Rostock, Germany
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Philip Van Damme
7University of Leuven, Leuven, Belgium
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Majid Hafezparast
2Neuroscience, School of Life Sciences, University of Sussex, Falmer, Brighton, England
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  • ORCID record for Majid Hafezparast
Keith W Caldecott
1Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, England
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  • ORCID record for Keith W Caldecott
  • For correspondence: k.w.caldecott@sussex.ac.uk
Published 26 February 2019. DOI: 10.26508/lsa.201800222
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Abstract

FUS (fused in sarcoma) plays a key role in several steps of RNA metabolism, and dominant mutations in this protein are associated with neurodegenerative diseases. Here, we show that FUS is a component of the cellular response to topoisomerase I (TOP1)–induced DNA breakage; relocalising to the nucleolus in response to RNA polymerase II (Pol II) stalling at sites of TOP1-induced DNA breaks. This relocalisation is rapid and dynamic, reversing following the removal of TOP1-induced breaks and coinciding with the recovery of global transcription. Importantly, FUS relocalisation following TOP1-induced DNA breakage is associated with increased FUS binding at sites of RNA polymerase I transcription in ribosomal DNA and reduced FUS binding at sites of RNA Pol II transcription, suggesting that FUS relocates from sites of stalled RNA Pol II either to regulate pre-mRNA processing during transcriptional stress or to modulate ribosomal RNA biogenesis. Importantly, FUS-mutant patient fibroblasts are hypersensitive to TOP1-induced DNA breakage, highlighting the possible relevance of these findings to neurodegeneration.

  • Received October 23, 2018.
  • Revision received February 13, 2019.
  • Accepted February 15, 2019.
  • © 2019 Martinez-Macias et al.
Creative Commons logoCreative Commons logohttps://creativecommons.org/licenses/by/4.0/

This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).

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FUS is a transcriptional stress response protein
Maria Isabel Martinez-Macias, Duncan AQ Moore, Ryan L Green, Fernando Gomez-Herreros, Marcel Naumann, Andreas Hermann, Philip Van Damme, Majid Hafezparast, Keith W Caldecott
Life Science Alliance Feb 2019, 2 (2) e201800222; DOI: 10.26508/lsa.201800222

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FUS is a transcriptional stress response protein
Maria Isabel Martinez-Macias, Duncan AQ Moore, Ryan L Green, Fernando Gomez-Herreros, Marcel Naumann, Andreas Hermann, Philip Van Damme, Majid Hafezparast, Keith W Caldecott
Life Science Alliance Feb 2019, 2 (2) e201800222; DOI: 10.26508/lsa.201800222
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Volume 2, No. 2
April 2019
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