Characterizing the MCT-1:DenR Complex, a Translational Enhancer for Lymphoma Survival

MCT-1 is an oncogene that is highly expressed in human lymphomas and has been linked to increased cell proliferation and decreased apoptosis through the enhanced translation of survival-related transcripts. Acting on mRNAs that house serial 5'-untranslated ORFs, MCT-1 is directly involved in translation initiation and ribosomal recycling via the formation of an active dimer with DenR (DRP) and aids in scanning for the translatable regions of the transcript. When combined, this dimer tethers together two RNA-binding domains, a PUA domain from MCT-1 and a SUI-1 domain from DenR that appear to anchor the complex at the 7-methyl guanosine cap and direct the reassociation of the 43S initiation complex at AUG start codons. The goal of this study has been the characterization of the structure of the MCT-1:DenR dimer and the thermodynamics behind complex formation using a combination of NMR, X-ray crystallography, and ITC with particular attention paid to the conformational changes in the loosely ordered N-terminal domain of DenR induced by dimer formation. Ultimately, the information gained from this study will be applied to the design and evaluation of perturbagens that interfere with dimer formation and the development of MCT-1 driven anti-apoptotic phenotypes, especially in refractory lymphomas.