2. Academic Validation
  3. FUS (fused in sarcoma) is a component of the cellular response to topoisomerase I-induced DNA breakage and transcriptional stress

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

  • Life Sci Alliance. 2019 Feb 26;2(2):e201800222. doi: 10.26508/lsa.201800222.
Maria Isabel Martinez-Macias 1,  Duncan Aq Moore 2,  Ryan L Green 3,  Fernando Gomez-Herreros 2 4,  Marcel Naumann 5 6,  Andreas Hermann 5 7 6,  Philip Van Damme 8,  Majid Hafezparast 3,  Keith W Caldecott 9
Affiliations

Affiliations

  • 1 Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, England mm761@sussex.ac.uk.
  • 2 Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, England.
  • 3 Neuroscience, School of Life Sciences, University of Sussex, Falmer, Brighton, England.
  • 4 Instituto de Biomedicina de Sevilla, Hospital Virgen del Rocio-Centro Superior de Investigaciones Cientificas-Universidad de Sevilla, Seville, Spain.
  • 5 Department of Neurology, Technische Universität Dresden, and German Center for Neurodegenerative Diseases (DZNE), Dresden, Germany.
  • 6 Translational Neurodegeneration Section "Albrecht-Kossel", Department of Neurology, University Medical Center Rostock, University of Rostock, Rostock, Germany.
  • 7 Center for Transdisciplinary Neurosciences Rostock, University Medical Center Rostock, University of Rostock, Rostock, Germany.
  • 8 University of Leuven, Leuven, Belgium.
  • 9 Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, England k.w.caldecott@sussex.ac.uk.
PMID: 30808650 DOI: 10.26508/lsa.201800222
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.

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