Martínez Macías, María IsabelGreen, Ryan L.Gómez Herreros, FernandoNaumann, MarcelHermann, AndreasHafezparast, MajidCaldecott, Keith W.Moore, Duncan A. Q.Damme, Philip Van2019-07-092019-07-092019-02-26Martínez Macías, M.I., Green, R.L., Gómez Herreros, F., Naumann, M., Hermann, A., Hafezparast, M.,...,Damme, P.V. (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-e201800222-14.2575-1077https://hdl.handle.net/11441/87960FUS (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 neurodegenerationapplication/pdfengAttribution-NonCommercial-NoDerivatives 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/articleinfo:eu-repo/semantics/openAccesshttps://doi.org/10.26508/lsa.201800222