e201800222.full.pdf (2.3 MB)
Download fileFUS (fused in sarcoma) is a component of the cellular response to topoisomerase I–induced DNA breakage and transcriptional stress
journal contribution
posted on 2023-06-12, 09:00 authored by Maria Isabel Martinez-Macias, Duncan MooreDuncan Moore, Ryan L Green, Fernando Gomez-Herreros, Marcel Naumann, Andreas Hermann, Philip Van Damme, Majid HafezparastMajid Hafezparast, Keith CaldecottKeith CaldecottFUS (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.
History
Publication status
- Published
File Version
- Published version
Journal
Life Science AllianceISSN
2575-1077Publisher
Life Science AllianceExternal DOI
Issue
2Volume
2Page range
1-14Article number
e201800222Department affiliated with
- Neuroscience Publications
Research groups affiliated with
- Neurodegenerative Disease and Ageing Research Centre Publications
- Sussex Neuroscience Publications
Full text available
- No
Peer reviewed?
- Yes