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

Martinez-Macias, Maria Isabel, Moore, Duncan A Q, Green, Ryan L, Gomez-Herreros, Fernando, Naumann, Marcel, Hermann, Andreas, Van Damme, Philip, Hafezparast, Majid and Caldecott, Keith W (2019) FUS (fused in sarcoma) is a component of the cellular response to topoisomerase I–induced DNA breakage and transcriptional stress. Life Science Alliance, 2 (2). e201800222 1-14. ISSN 2575-1077

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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.

Item Type: Article
Keywords: Motor Neuron Disease, Amyotrophic lateral sclerosis, FUS/TLS, DNA damage, Topoisomerase, Neurodegeneration, Transcription,
Schools and Departments: School of Life Sciences > Neuroscience
School of Life Sciences > Sussex Centre for Genome Damage and Stability
Research Centres and Groups: Neurodegenerative Disease and Ageing Research Centre
Sussex Neuroscience
Subjects: Q Science
Q Science > Q Science (General) > Q0179.9 Research
Q Science > Q Science (General)
Related URLs:
Depositing User: Majid Hafezparast
Date Deposited: 18 Feb 2019 10:13
Last Modified: 23 May 2019 16:12
URI: http://sro.sussex.ac.uk/id/eprint/81954

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