Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, England
Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, England.
Life Sci Alliance. 2019 Feb 26;2(2). doi: 10.26508/lsa.201800222. Print 2019 Apr.
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.
融合在肉瘤中（FUS）在 RNA 代谢的几个步骤中发挥关键作用，该蛋白的显性突变与神经退行性疾病有关。在这里，我们表明 FUS 是细胞对拓扑异构酶 I（TOP1）诱导的 DNA 断裂的反应的组成部分；在 RNA 聚合酶 II（Pol II）在 TOP1 诱导的 DNA 断裂位点处停滞时，重新定位到核仁。这种重定位是快速和动态的，在去除 TOP1 诱导的断裂后逆转，并与全局转录的恢复同时发生。重要的是，TOP1 诱导的 DNA 断裂后 FUS 的重定位与 RNA 聚合酶 I 在核糖体 DNA 中转录时 FUS 结合增加以及 RNA Pol II 转录部位 FUS 结合减少有关，这表明 FUS 从停滞的 RNA Pol II 部位重新定位，要么是为了在转录应激期间调节前体 mRNA 加工，要么是为了调节核糖体 RNA 生物发生。重要的是，FUS 突变患者成纤维细胞对 TOP1 诱导的 DNA 断裂高度敏感，这突出了这些发现与神经退行性变的可能相关性。
