Martinez-Macias, Maria IsabelMoore, Duncan AqGreen, Ryan LGomez-Herreros, FernandoNaumann, MarcelHermann, AndreasVan Damme, PhilipHafezparast, MajidCaldecott, Keith W2023-01-252023-01-252019-02-26http://hdl.handle.net/10668/13629FUS (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.enAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/A549 CellsAmyotrophic Lateral SclerosisAnimalsBinding SitesBrainChromatinDNA Breaks, Double-StrandedDNA RepairDNA Topoisomerases, Type IFibroblastsHeLa CellsHumansMiceMutant ProteinsMutationNeural Stem CellsNeuronsRNA Polymerase IRNA Polymerase IIRNA-Binding Protein FUSTranscription, Geneticresearch article30808650open access10.26508/lsa.2018002222575-1077PMC6391683https://www.life-science-alliance.org/content/lsa/2/2/e201800222.full.pdfhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391683/pdf