FIR:FUSE COMPLEX

冷杉：融合复合体

• 批准号: 7358920
• 负责人: DEMETRIOS BRADDOCK
• 金额: $ 0.45万
• 依托单位: BROOKHAVEN SCIENCE ASSOC-BROOKHAVEN LAB
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7358920
• 关键词: FIR; FUSE; COMPLEX

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. C-myc is an essential oncogene which is lethal if improperly controlled. The Fuse Binding Protein (FBP) binds a single stranded DNA (ssDNA) sequence upstream of the c-myc promoter named the Far Upstream Element (FUSE), and increases transcription of the oncogene by stimulating the helicase activity of TFIIH. FBP recognizes its target DNA sequences via K homology (KH) repeats located in the central domain of the protein. A demonstration of FBP¿¿¿s controlling influence on c-myc is seen in dominant negative mutants of FBP comprised of this DNA binding domain, which stops cell growth and shuts down c-myc expression in cancer cells in vitro. The FBP Interacting Repressor (FIR) modulates FBP¿¿¿s activation of c-myc by binding to FBP and FUSE, resulting in repression of c-myc transcription by reducing TFIIH helicase activity. The molecular details of FIR¿¿¿s modulation of c-myc activity is not know, and is the primary motivation for determining the structure of FIR bound to FUSE. FIR repression of the activating FBP:FUSE complex is uncoupled in the widely studied human malignancy Xeroderma Pigmentosum. Therefore, determining the three dimensional structure of FIR bound to FUSE will provide insight into the genetic regulation of a central oncogene (c-myc), and shed light into the pathogenesis of an actively studied human disease and model of oncogenesis (Xeroderma-Pigmentosum).

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心机构，不一定为研究者机构。C-myc是一种重要的癌基因，如果控制不当，它是致命的。TFIIH结合蛋白（FBP）结合c-myc启动子上游的单链DNA（ssDNA）序列，称为远上游元件（FUSE），并通过刺激TFIIH的解旋酶活性来增加癌基因的转录。FBP通过位于蛋白质中心结构域的K同源（KH）重复序列识别其靶DNA序列。一个示范的FBP？¿¿在由该DNA结合结构域组成的FBP显性阴性突变体中观察到对c-myc的控制影响，其在体外停止细胞生长并关闭癌细胞中c-myc的表达。FBP相互作用抑制因子（FIR）通过与FBP和FUSE结合调节FBP对c-myc的激活，从而通过降低TFIIH解旋酶活性抑制c-myc转录。FIR的分子细节¿¿ c-myc活性的调节是未知的，这是确定与FUSE结合的FIR结构的主要动机。在广泛研究的人类恶性着色性干皮病中，激活的FBP：FUSE复合物的FIR抑制是解偶联的。因此，确定FIR结合FUSE的三维结构，将提供深入了解中央癌基因（c-myc）的遗传调控，并揭示了积极研究的人类疾病和肿瘤发生模型（干皮病-色素性皮肤病）的发病机制。