RT Journal Article
SR Electronic
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
FD Life Science Alliance LLC
SP e201800222
DO 10.26508/lsa.201800222
VO 2
IS 2
A1 Maria Isabel Martinez-Macias
A1 Duncan AQ Moore
A1 Ryan L Green
A1 Fernando Gomez-Herreros
A1 Marcel Naumann
A1 Andreas Hermann
A1 Philip Van Damme
A1 Majid Hafezparast
A1 Keith W Caldecott
YR 2019
UL https://www.life-science-alliance.org/content/2/2/e201800222.abstract
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.