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
  • 1. Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, England [email protected].
  • 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 [email protected].
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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