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FUS oncofusion protein condensates recruit mSWI/SNF chromatin remodeler via heterotypic interactions between prion-like domains
Protein Science ( IF 4.5 ) Pub Date : 2021-05-21 , DOI: 10.1002/pro.4127
Richoo B Davis 1 , Taranpreet Kaur 1 , Mahdi Muhammad Moosa 1 , Priya R Banerjee 1
Affiliation  

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.

中文翻译:


FUS 肿瘤融合蛋白凝聚物通过朊病毒样结构域之间的异型相互作用招募 mSWI/SNF 染色质重塑剂



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多种癌症的常见驱动因素。 FET(FUS、EWSR1 和 TAF15)家族蛋白的肿瘤融合是由 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) 融合引起的,并且与异常转录程序有关通过与染色质重塑者的相互作用。在这里,我们证明 FUS-DDIT3(一种 FET 肿瘤融合蛋白)经历 PLD 介导的相分离,形成液体状冷凝物。核 FUS-DDIT3 凝聚物可以招募全局转录机制的重要组成部分,例如染色质重塑器 SWI/SNF。哺乳动物 SWI/SNF (mSWI/SNF) 的募集是由 FUS-DDIT3 和 SWI/SNF 核心亚基(例如催化成分 BRG1)之间的异型 PLD-PLD 相互作用驱动的。使用单分子相关力荧光显微镜进行的进一步实验支持了一个模型,其中融合蛋白在 DNA 表面形成凝聚物并富集 BRG1,以通过异位染色质重塑激活转录。类似的 PLD 驱动的 mSWI/SNF 与转录因子的共缩合可以被其他具有通用 PLD-DBD 结构域结构的致癌融合蛋白用于全局转录重编程。
更新日期:2021-06-13
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