Role of Phase separation by fusion oncoproteins in oncogenesis

摘要 融合两个不同基因片段(称为双亲)的基因易位是已知的驱动因素 无数癌症中的致癌作用。框内易位的表达产生融合癌蛋白(FOS)与 混合功能特性异常地控制关键的生物过程，并最终导致 不加控制的细胞增殖和肿瘤发生。Fos通常是融合在一起的异常转录因子 作为DNA或染色质结合的激活域的一个亲本的非结构化片段 他者的领地。这些Fos导致异常的基因表达，使细胞转化并驱动 致癌作用。我们的初步计算结果表明，FOS通常包含本质上的无序 显示与经历液-液相能力相关的序列特征的区域(IDR) 分离(LLP)，这一过程现在被认为是调节许多细胞的形成和功能的过程 小体，包括无膜细胞器，更重要的是，核转录中心有斑点 形态学。 我们对数千个临床记录的融合癌基因的计算分析表明， 相关FOS的很大一部分包含易于LLP的IDR。基于这一观察，我们假设 一组fos通过相分离形成异常转录中心来改变细胞；其他fos 含有LLP的IDR可能会形成具有不同功能的异常细胞点。此外，我们 假设FOS代表丰富的蛋白质来源，通过细胞内和体外的分析，以及 通过计算分析，将揭示与之相关的新序列和构象特征 相分离。这些假设将通过三个具体目标进行检验。

SUMMARY Gene translocations that fuse segments of two different genes (termed parents) are known to drive oncogenesis in myriad cancers. Expression of in-frame translocations yields fusion oncoproteins (FOs) with hybrid functional properties that aberrantly control critical biological processes and, ultimately, cause unchecked cell proliferation and oncogenesis. FOs are often abnormal transcription factors that fuse unstructured segments of one parent that function as activation domains to a DNA or chromatin binding domain of the other. These FOs result in abnormal gene expression that transforms cells and drives oncogenesis. Our preliminary computational results show that FOs often contain intrinsically disordered regions (IDRs) that display sequence features associated with the ability to undergo liquid-liquid phase separation (LLPS), a process now appreciated to mediate the formation and function of numerous cellular bodies, including membrane-less organelles and, importantly, nuclear transcription centers with punctate morphology. Our computational analyses of thousands of clinically documented fusion oncogenes show that a significant portion of the associated FOs contain LLPS-prone IDRs. Based on this observation, we hypothesize that a set of FOs transform cells by forming aberrant transcription centers through phase separation; other FOs containing LLPS-prone IDRs may form aberrant cellular puncta that host different functions. Further, we hypothesize that FOs represent a rich source of proteins which, through analysis in cells and in vitro, and through computational analyses, will reveal novel sequence and conformational features associated with phase separation. These hypotheses will be tested through three specific aims.