Role of Phase separation by fusion oncoproteins in oncogenesis

融合癌蛋白相分离在肿瘤发生中的作用

• 批准号: 10066334
• 负责人: Ashok A Deniz
• 金额: $ 65.94万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-06 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10066334
• 关键词: Address; Algorithms; Amino Acid Sequence; Binding; Biological Process; Biophysics; Cell Nucleus; Cell Proliferation; Cells; Childhood Leukemia; Chromatin; Clinical; Code; Computer Analysis; DNA; DNA Polymerase II; DNA-Directed RNA Polymerase; Data; Disease; Distal; EWS-FLI1 fusion protein; Elements; Enhancers; Fusion Oncogene Proteins; Future; Gene Abnormality; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Gene Fusion; Genes; Genetic Transcription; Genomic Segment; HOXA9 gene; Hematopoietic; Homeobox Genes; Hybrids; In Vitro; Information Resources; Link; Liquid substance; Malignant Neoplasms; Mediating; Membrane; Molecular Conformation; Morphology; NUP98 gene; Nuclear; Nucleic Acids; Oncogenes; Oncogenic; Optics; Organelles; Parents; Phase; Phenotype; Process; Property; Protein Region; Proteins; Recurrence; Role; Saint Jude Children' s Research Hospital; Source; Structure; Testing; Transcriptional Regulation; Translating; base; cell transformation; gene translocation; genomic data; lens; novel; promoter; protein function; protein protein interaction; sarcoma; submicron; transcription factor; tumorigenesis

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.

总结 基因易位融合两个不同基因（称为父母）的片段， 无数癌症的肿瘤发生。框内易位的表达产生融合癌蛋白（FO）， 杂合功能特性，异常地控制关键的生物过程，并最终导致 不受控制的细胞增殖和肿瘤发生。FO通常是异常的转录因子， 一个亲本的非结构化片段，作为DNA或染色质结合的激活结构域 对方的领域。这些FO导致异常的基因表达，转化细胞并驱动 肿瘤发生我们的初步计算结果表明，FOs往往包含本征无序 显示与经历液-液相转化的能力相关的序列特征的区域（IDR 分离（LLPS），一个现在被认为介导许多细胞的形成和功能的过程， 体，包括无膜细胞器，重要的是，核转录中心与点状 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FO的显著部分含有LLPS倾向的IDR。基于这一观察，我们假设 一组FO通过相分离形成异常转录中心来转化细胞;其他FO 含有LLPS倾向的IDR可能形成具有不同功能的异常细胞斑点。我们还 假设FO代表丰富蛋白质来源，通过细胞和体外分析， 通过计算分析，将揭示新的序列和构象特征， 相分离。这些假设将通过三个具体目标进行检验。