FIR:FUSE COMPLEX

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。C-myc是一种重要的癌基因，如果控制不当是致命的。融合蛋白结合蛋白与c-myc启动子上游的单链DNA序列结合，称为远上游元件(FUSE)，通过刺激TFIIH的解旋酶活性来促进癌基因的转录。FBP通过位于蛋白质中心区域的K同源(KH)重复序列识别其靶DNA序列。在含有该DNA结合域的FBP的显性负突变体中，证明了FBP对c-myc的控制作用。在体外，FBP可以阻止细胞生长并关闭c-myc的表达。FBP相互作用抑制子(FIR)通过与FBP和FUSE结合来调节FBP对c-myc的激活，从而通过降低TFIIH解旋酶活性来抑制c-myc的转录。FIR S调控c-myc活性的分子细节尚不清楚，这是确定FIR结合融合结构的主要动机。FIR抑制活化的FBP：融合复合体在被广泛研究的人类恶性着色性干皮病中是解偶联的。因此，确定FIR结合的三维结构将有助于深入了解中枢癌基因(c-myc)的遗传调控，并有助于揭示一种活跃研究的人类疾病和肿瘤发生模型(干皮病-色素变性)的发病机制。

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).