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

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 nucleo...

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Autores principales: Martinez-Macias, Maria Isabel, Moore, Duncan AQ, Green, Ryan L, Gomez-Herreros, Fernando, Naumann, Marcel, Hermann, Andreas, Van Damme, Philip, Hafezparast, Majid, Caldecott, Keith W
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Life Science Alliance LLC 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391683/
https://www.ncbi.nlm.nih.gov/pubmed/30808650
http://dx.doi.org/10.26508/lsa.201800222
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author Martinez-Macias, Maria Isabel
Moore, Duncan AQ
Green, Ryan L
Gomez-Herreros, Fernando
Naumann, Marcel
Hermann, Andreas
Van Damme, Philip
Hafezparast, Majid
Caldecott, Keith W
author_facet Martinez-Macias, Maria Isabel
Moore, Duncan AQ
Green, Ryan L
Gomez-Herreros, Fernando
Naumann, Marcel
Hermann, Andreas
Van Damme, Philip
Hafezparast, Majid
Caldecott, Keith W
author_sort Martinez-Macias, Maria Isabel
collection PubMed
description 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.
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spelling pubmed-63916832019-02-28 FUS (fused in sarcoma) is a component of the cellular response to topoisomerase I–induced DNA breakage and transcriptional stress Martinez-Macias, Maria Isabel Moore, Duncan AQ Green, Ryan L Gomez-Herreros, Fernando Naumann, Marcel Hermann, Andreas Van Damme, Philip Hafezparast, Majid Caldecott, Keith W Life Sci Alliance Research Articles 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. Life Science Alliance LLC 2019-02-26 /pmc/articles/PMC6391683/ /pubmed/30808650 http://dx.doi.org/10.26508/lsa.201800222 Text en © 2019 Martinez-Macias et al. https://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Articles
Martinez-Macias, Maria Isabel
Moore, Duncan AQ
Green, Ryan L
Gomez-Herreros, Fernando
Naumann, Marcel
Hermann, Andreas
Van Damme, Philip
Hafezparast, Majid
Caldecott, Keith W
FUS (fused in sarcoma) is a component of the cellular response to topoisomerase I–induced DNA breakage and transcriptional stress
title FUS (fused in sarcoma) is a component of the cellular response to topoisomerase I–induced DNA breakage and transcriptional stress
title_full FUS (fused in sarcoma) is a component of the cellular response to topoisomerase I–induced DNA breakage and transcriptional stress
title_fullStr FUS (fused in sarcoma) is a component of the cellular response to topoisomerase I–induced DNA breakage and transcriptional stress
title_full_unstemmed FUS (fused in sarcoma) is a component of the cellular response to topoisomerase I–induced DNA breakage and transcriptional stress
title_short FUS (fused in sarcoma) is a component of the cellular response to topoisomerase I–induced DNA breakage and transcriptional stress
title_sort fus (fused in sarcoma) is a component of the cellular response to topoisomerase i–induced dna breakage and transcriptional stress
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391683/
https://www.ncbi.nlm.nih.gov/pubmed/30808650
http://dx.doi.org/10.26508/lsa.201800222
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