FUS oncofusion protein condensates recruit mSWI/SNF chromatin remodeler via heterotypic interactions between prion-like domains
FUS oncofusion protein condensates recruit mSWI/SNF chromatin remodeler via heterotypic interactions between prion-like domains
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DOI：
10.1002/pro.4127
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发表时间：
2021-06-04
期刊：
影响因子：
8
通讯作者：
Banerjee, Priya R.
中科院分区：
文献类型：
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作者：
Davis, Richoo B.;Kaur, Taranpreet;Banerjee, Priya R.
由基因组易位产生的融合转录因子是包括肉瘤和白血病在内的几种类型癌症的常见驱动因素。FET（FUS、EWSR 1和TAF 15）家族蛋白的肿瘤融合由FET蛋白的朊病毒样结构域（PLD）与某些转录调节因子的DNA结合结构域（DBD）的融合引起，并且通过与染色质重塑物的相互作用而涉及异常转录程序。在这里，我们表明，FUS-DDIT 3，一个FET癌融合蛋白，经历PLD介导的相分离成液体样的冷凝物。核FUS-DDIT 3缩合物可以募集全球转录机制的重要组成部分，如染色质重塑SWI/SNF。哺乳动物SWI/SNF（mSWI/SNF）的募集由FUS-DDIT 3与SWI/SNF的核心亚基（例如催化组分BRG 1）之间的异型PLD-PLD相互作用驱动。进一步的实验与单分子相关的力荧光显微镜支持的模型，其中融合蛋白在DNA表面形成缩合物，并丰富BRG 1激活转录的异位染色质重塑。类似的PLD驱动的mSWI/SNF与转录因子的共缩合可以被具有通用PLD-DBD结构域架构的其他致癌融合蛋白用于全局转录重编程。
Fusion transcription factors generated by genomic translocations are common drivers of several types of cancers including sarcomas and leukemias. Oncofusions of the FET (FUS, EWSR1, and TAF15) family proteins result from the fusion of the prion-like domain (PLD) of FET proteins to the DNA-binding domain (DBD) of certain transcription regulators and are implicated in aberrant transcriptional programs through interactions with chromatin remodelers. Here, we show that FUS-DDIT3, a FET oncofusion protein, undergoes PLD-mediated phase separation into liquid-like condensates. Nuclear FUS-DDIT3 condensates can recruit essential components of the global transcriptional machinery such as the chromatin remodeler SWI/SNF. The recruitment of mammalian SWI/SNF (mSWI/SNF) is driven by heterotypic PLD-PLD interactions between FUS-DDIT3 and core subunits of SWI/SNF, such as the catalytic component BRG1. Further experiments with single-molecule correlative force-fluorescence microscopy support a model wherein the fusion protein forms condensates on DNA surface and enrich BRG1 to activate transcription by ectopic chromatin remodeling. Similar PLD-driven co-condensation of mSWI/SNF with transcription factors can be employed by other oncogenic fusion proteins with a generic PLD-DBD domain architecture for global transcriptional reprogramming.