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FUS (fused in sarcoma) is a component of the cellular response to topoisomerase I–induced DNA breakage and transcriptional stress

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Version 2 2023-06-12, 09:00
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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 Caldecott
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.

History

Publication status

  • Published

File Version

  • Published version

Journal

Life Science Alliance

ISSN

2575-1077

Publisher

Life Science Alliance

Issue

2

Volume

2

Page range

1-14

Article number

e201800222

Department 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

Legacy Posted Date

2019-02-18

First Open Access (FOA) Date

2019-02-18

First Compliant Deposit (FCD) Date

2019-02-14

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