Date of Graduation

12-2009

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Cell & Molecular Biology (PhD)

Degree Level

Graduate

Department

Cell & Molecular Biology

Advisor/Mentor

McNabb, David S.

Committee Member

Deaton, Russell J.

Second Committee Member

Korth, Kenneth L.

Third Committee Member

Rhoads, Douglas D.

Keywords

CCAAT; Candida albicans; Hap complex; Transcription

Abstract

The CCAAT-binding factor is a heterooligomeric transcription factor that is evolutionarily conserved in eukaryotes. In yeast, the DNA-binding component that interacts with the CCAAT consensus sequence in promoters consists of the subunits termed Hap2p, Hap3p and Hap5p. In yeast and fungi, a fourth subunit, Hap4p, is required for regulating gene expression. The goal of this research is to understand the function of the Candida albicans CCAAT-binding factor and how it relates to virulence and pathogenicity. C. albicans is a human opportunistic pathogen responsible for a variety of mucosal and systemic infections that result in significant morbidity and mortality, particularly in immunosuppressed individuals. C. albicans responds to environmental changes by altering its morphology between the yeast and hyphal forms during infection, and the ability to transition between the two forms is required for virulence. We have previously demonstrated that C. albicans hap5delta/hap5delta mutants are defective in the yeast-to-hyphal transition in vitro under several conditions and become hyperfilamentous when deprived of glucose as a sole carbon source (Eukaryotic Cell 4:1662-1676, 2005). Moreover, the hap5delta/hap5delta mutant shows no CCAAT-binding activity, suggesting the lost of the CCAAT-binding factor alters the ability of cells to undergo the normal yeast-to-hyphal transition. This research will show that the hap2delta/hap2delta mutant also abolishes DNA-binding activity and exhibits the same phenotypic deficiencies as hap5delta/hap5deltamutants. Two distinct functional homologs of S. cerevisiae Hap3p have been identified in C. albicans, designated Hap31p and Hap32p. These subunits form separate CCAAT-binding complexes with Hap2p/Hap5p. Hap31p is a member of the complex under iron replete conditions and Hap32 under low iron conditions. The Hap complex effects the regulation of CYC1 and COX5. Also three distinct homologs of S. cerevisiae Hap4p have been identified in C. albicans, designated Hap41p, Hap42p, and Hap43p.

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