RT Journal Article
T1 FUS (fused in sarcoma) is a component of the cellular response to topoisomerase I-induced DNA breakage and transcriptional stress.
A1 Martinez-Macias, Maria Isabel
A1 Moore, Duncan Aq
A1 Green, Ryan L
A1 Gomez-Herreros, Fernando
A1 Naumann, Marcel
A1 Hermann, Andreas
A1 Van Damme, Philip
A1 Hafezparast, Majid
A1 Caldecott, Keith W
AB 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.
YR 2019
FD 2019-02-26
LK http://hdl.handle.net/10668/13629
UL http://hdl.handle.net/10668/13629
LA en
DS RISalud
RD Apr 7, 2025