@article {Martinez-Maciase201800222, author = {Maria Isabel Martinez-Macias and Duncan AQ Moore and Ryan L Green and Fernando Gomez-Herreros and Marcel Naumann and Andreas Hermann and Philip Van Damme and Majid Hafezparast and Keith W Caldecott}, title = {FUS (fused in sarcoma) is a component of the cellular response to topoisomerase I{\textendash}induced DNA breakage and transcriptional stress}, volume = {2}, number = {2}, elocation-id = {e201800222}, year = {2019}, doi = {10.26508/lsa.201800222}, publisher = {Life Science Alliance}, 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){\textendash}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.}, URL = {https://www.life-science-alliance.org/content/2/2/e201800222}, eprint = {https://www.life-science-alliance.org/content/2/2/e201800222.full.pdf}, journal = {Life Science Alliance} }