DNA-binding domain as the minimal region driving RNA-dependent liquid-liquid phase separation of androgen receptor
DNA-binding domain as the minimal region driving RNA-dependent liquid-liquid phase separation of androgen receptor
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DOI：
10.1002/pro.4100
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发表时间：
2021-05-07
期刊：
影响因子：
8
通讯作者：
Tompa, Peter
中科院分区：
文献类型：
--
作者：
Ahmed, Junaid;Meszaros, Attila;Tompa, Peter
雄激素受体（AR）是一种核激素受体，调节睾丸、前列腺和神经系统发育相关基因的转录。AR的失调是前列腺癌（PC）的主要驱动因素。全长AR的主要激动剂是睾酮，而其剪接变体，例如与癌症有关的AR-v7可能缺乏配体结合结构域，因此缺乏适当的激素控制。最近，已经证明全长AR，而不是AR-v7，可以在PC的细胞模型中经历液-液相分离（LLPS）。在详细的生物信息学和缺失分析中，我们分析了哪个AR区域负责LLPS。我们发现它的DNA结合结构域（DBD）可以结合RNA，并可以进行RNA依赖性LLPS。RNA以可重入的方式调节其LLPS，即在较高浓度下具有抑制作用。由于RNA比DNA更弱地结合DBD，而RNA和DNA都定位于AR液滴中，因此其LLPS取决于两种核酸的相对浓度。紧接DBD之前的区域对AR的LLPS倾向没有影响，而其长N-末端无序反式激活结构域的功能部分称为激活功能1（AF 1）抑制AR-v7相分离。我们认为，由此产生的AR-v7的LLPS趋势减少可能有助于在前列腺癌中AR的转录功能的失调。
Androgen receptor (AR) is a nuclear hormone receptor that regulates the transcription of genes involved in the development of testis, prostate and the nervous system. Misregulation of AR is a major driver of prostate cancer (PC). The primary agonist of full-length AR is testosterone, whereas its splice variants, for example, AR-v7 implicated in cancer may lack a ligand-binding domain and are thus devoid of proper hormonal control. Recently, it was demonstrated that full-length AR, but not AR-v7, can undergo liquid-liquid phase separation (LLPS) in a cellular model of PC. In a detailed bioinformatics and deletion analysis, we have analyzed which AR region is responsible for LLPS. We found that its DNA-binding domain (DBD) can bind RNA and can undergo RNA-dependent LLPS. RNA regulates its LLPS in a reentrant manner, that is, it has an inhibitory effect at higher concentrations. As RNA binds DBD more weakly than DNA, while both RNA and DNA localizes into AR droplets, its LLPS depends on the relative concentration of the two nucleic acids. The region immediately preceding DBD has no effect on the LLPS propensity of AR, whereas the functional part of its long N-terminal disordered transactivation domain termed activation function 1 (AF1) inhibits AR-v7 phase separation. We suggest that the resulting diminished LLPS tendency of AR-v7 may contribute to the misregulation of the transcription function of AR in prostate cancer.