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

Maria Isabel Martinez-Macias,Andreas Hermann,Philip Van Damme,Keith W Caldecott,Duncan Aq Moore,Fernando Gomez-Herreros,Majid Hafezparast,Marcel Naumann,Ryan L Green

doi:10.26508/lsa.201800222

Maria Isabel Martinez-Macias, Andreas Hermann + Show 7 more

Open Access

https://doi.org/10.26508/lsa.201800222

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Abstract

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.

Highlights

Amyotrophic lateral sclerosis (ALS) is a motor neuron disease with significant phenotypic variability but with some common pathological and genetic characteristics
fused in sarcoma (FUS) is a heterogeneous nuclear ribonucleoprotein that belongs to the FET/TET family of RNA-binding proteins, including TAF15 and EWS [15, 16, 17, 18]
It has been reported that siRNA-mediated depletion of FUS results in reduced DNA double-strand breaks (DSBs) repair and that FUS is involved in this process [21, 23]

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a motor neuron disease with significant phenotypic variability but with some common pathological and genetic characteristics (reviewed in references 1, 2, 3). Mutations in several additional RNA-binding proteins have been associated with neurodegenerative diseases, including EWS (EWSR1), TAF15 [8], hnRNPA1, hnRNP A2B1 [9], and ataxin-2 [10], supporting the notion that defects in RNA metabolism can induce neurodegeneration [11, 12, 13]. FUS is a heterogeneous nuclear ribonucleoprotein (hnRNP) that belongs to the FET/TET family of RNA-binding proteins, including TAF15 and EWS [15, 16, 17, 18]. FUS modulates multiple aspects of RNA metabolism, including transcription, splicing, microRNA processing, and mRNA transport (reviewed in references 18, 19, 20). It has been proposed that ALS mutations cause pathological changes in FUSregulated gene expression and RNA processing, due either to loss of normal FUS function, toxic gain of function, or both

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