Dissertations, Theses, and Capstone Projects

Date of Degree

6-2025

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy

Program

Biochemistry

Advisor

Dixie J. Goss

Committee Members

Ruben L. Gonzalez Jr.

Kevin H. Gardner

Hualin Zhong

Akira Kawamura

Subject Categories

Biochemistry | Bioinformatics | Biophysics | Cancer Biology | Molecular Biology | Structural Biology

Keywords

Hypoxia, 5 prime untranslated region, cellular stress, translation initiation, eIF4E-independent, eukaryotic Initiation Factor

Abstract

Translation initiation in eukaryotes is a highly regulated process essential for accurate protein synthesis. It is a dynamic process that involves a complex interplay between messenger RNAs (mRNAs), ribosomal subunits, and a host of initiation factors, ensuring precise start codon selection and the subsequent assembly of the translation machinery. This process has well been known to be mediated by the eukaryotic Initiation Factor (eIF4F), which consists of the cap binding protein eIF4E, the scaffolding protein eIF4GI, and the helicase factor eIF4A.The recognition and binding of eIF4E to the m7G cap structure of the mRNA is essential for the subsequent recruitment of eIF4GI and eIF4A to form a translationally active eIF4F complex. During stress conditions in the cell such as hypoxia, nutrient limitation and viral infection, eIF4E is sequestered by 4E-Binding Protein 1 (4E-BP1), a negative regulator of eIF4E activity. As such, the formation of a translationally active eIF4F complex is impaired, leading to a down regulation of translation. The discovery of eIF3d, an alternative cap-binding protein has been a remarkable addition to the field. However, studies on this novel protein are rather limited. In this study, we shed more light on how eIF3d and its direct binding partner DAP5 are able to co-ordinate with each other to drive the cap-dependent but eIF4E independent mechanism of translation of specific mRNA subsets. We present the first known quantitative and mechanistic studies involving the eukaryotic Initiation Factor 3d (eIF3d). The latter half of this manuscript delves into the additional eukaryotic initiation factor requirements of different structured mRNA subsets for DAP5 recruitment. This study adds new dimensions to our understanding of eIF4E independent mechanisms of translation initiation, with insights that may pave the way for future therapeutic interventions. These therapeutic interventions may involve targeting specific steps in this process, offering potential treatments for diseases that may be associated with aberrant protein synthesis.

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