TY - JOUR T1 - FUS (fused in sarcoma) is a component of the cellular response to topoisomerase I–induced DNA breakage and transcriptional stress JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.201800222 VL - 2 IS - 2 SP - e201800222 AU - Maria Isabel Martinez-Macias AU - Duncan AQ Moore AU - Ryan L Green AU - Fernando Gomez-Herreros AU - Marcel Naumann AU - Andreas Hermann AU - Philip Van Damme AU - Majid Hafezparast AU - Keith W Caldecott Y1 - 2019/04/01 UR - https://www.life-science-alliance.org/content/2/2/e201800222.abstract N2 - 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. ER -