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).
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