All ETDs from UAB

Advisory Committee Chair

James F Collawn

Advisory Committee Members

Eric J Sorscher

David A Schneider

Kasturi Mitra

Document Type

Dissertation

Date of Award

2018

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

In frame deletion of the phenylalanine residue at position 508 of the cystic fibrosis transmembrane conductance regulator (CFTR-ΔF508) results in protein misfolding and degradation, which reduces expression and function at the plasma membrane. The resulting loss of chloride and bicarbonate transport is the molecular basis of cystic fibrosis (CF). The F508-analogous mutation in the yeast oligomycin resistance 1 gene, yor1-ΔF670, has the same molecular consequences, but the phenotypic consequence is reduced resistance to growth inhibition by oligomycin. Comprehensive, systematic and quantitative analysis Yor1-ΔF gene modifiers has been demonstrated as a powerful way to further characterize known and to discover novel aspects of CFTR- ΔF508 biogenesis pathways. Rpl12, a component of the large ribosomal subunit stalk structure, is a novel, evolutionarily conserved modifiers of CFTR-ΔF biogenesis discovered by the Yor1-ΔF670 phenomic model. The focus of this investigation is to gain insight into how Rpl12 influences global gene interactions in the context of ΔF-protein biogenesis. Our hypothesis is that Rpl12 depletion changes the context for ΔF-protein biogenesis, within which new modifiers, additive effects, and synergistic targets to improve ΔF protein biogenesis can emerge. We performed multiple genome-wide screens specifically designed to investigate this idea, using an unbiased quantitative methodology of phenotyping and an analysis approach to delineate a global Rpl12 epistatic network that modulates ΔF-protein biogenesis. The phenomics approach teaches us how multiple modifier genes function together as a network to regulate ΔF biogenesis, providing new insight regarding the genomic potential for buffering disease phenotypes.

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