FUS (fused in sarcoma) is a component of the cellular response to topoisomerase I–induced DNA breakage and transcriptional stress
| Autor: | Fernando Gómez-Herreros, Philip Van Damme, Marcel Naumann, Duncan A. Q. Moore, María Isabel Martínez-Macías, Ryan L. Green, Majid Hafezparast, Andreas Hermann, Keith W. Caldecott |
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| Přispěvatelé: | Instituto de Biomedicina de Sevilla (IBIS), European Research Council, EMBO |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Life Sciences & Biomedicine - Other Topics
0301 basic medicine DNA Repair Transcription Genetic TDP-43 Nucleolus Health Toxicology and Mutagenesis metabolism [DNA Topoisomerases Type I] RNA polymerase II Plant Science metabolism [Neural Stem Cells] Q1 AMYOTROPHIC-LATERAL-SCLEROSIS Mice 0302 clinical medicine Neural Stem Cells Transcription (biology) RNA Polymerase I DNA Breaks Double-Stranded TOP1 protein human Research Articles metabolism [RNA-Binding Protein FUS] Neurons ROLES Ecology biology Chemistry BINDING PROTEINS FUS protein mouse Brain metabolism [RNA Polymerase I] Chromatin 3. Good health Cell biology genetics [Amyotrophic Lateral Sclerosis] DNA Topoisomerases Type I metabolism [Neurons] metabolism [RNA Polymerase II] COMPLEXES RNA Polymerase II Life Sciences & Biomedicine FUS/TLS metabolism [Fibroblasts] Research Article DNA repair metabolism [Chromatin] INSTABILITY RNA-POLYMERASE-II Q0179.9 genetics [Mutation] Biochemistry Genetics and Molecular Biology (miscellaneous) 03 medical and health sciences embryology [Brain] ddc:570 RNA polymerase I Animals Humans Binding site pathology [Amyotrophic Lateral Sclerosis] Biology SPINOCEREBELLAR ATAXIA Science & Technology Binding Sites MUTATIONS Topoisomerase cytology [Brain] Amyotrophic Lateral Sclerosis Ribosomal RNA FUS protein human Fibroblasts 030104 developmental biology A549 Cells Mutation biology.protein RNA-Binding Protein FUS Mutant Proteins genetics [RNA-Binding Protein FUS] 030217 neurology & neurosurgery HeLa Cells |
| Zdroj: | Life Science Alliance idUS. Depósito de Investigación de la Universidad de Sevilla instname Digital.CSIC. Repositorio Institucional del CSIC Life science alliance 2(2), e201800222 (2019). doi:10.26508/lsa.201800222 |
| ISSN: | 2575-1077 |
| DOI: | 10.26508/lsa.201800222 |
| Popis: | 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. This work was funded by an MRC project grant to KW Caldecott and M Hafezparast (MR/K01854X/1), and MRC and ERC Programme grants to KW Caldecott (ERC SIDSCA 694996, MR/P010121/1). MI Martinez-Macias was also supported by an European Molecular Biology Organisation (EMBO) Long-Term Fellowship ALTF 751-2013. |
| Databáze: | OpenAIRE |
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