The HMG Box defines a newly recognized family of eukaryotic transcription factors of broad relevance to the regulation of gene expression in human development and disease. Family members participate in a variety of clinical contexts, including immunology (regulation of T-cell receptor expression, lymphoid ontogeny, and HIV-1), diabetes mellitus (regulation of insulin-responsive metabolic enzymes), and oxidative metabolism (regulation of mitochondrial enzymes). Homologous factors function in yeast (Saccharomyces pombe) and fruit fly (Drosophila melanogaster). This application focuses on SRY, a family member of outstanding interest in relation to human sexual development. SRY, encoded by the mammalian Y chromosome, directs testicular differentiation of the indifferent gonad and thus regulates a genetic switch between male and female pathways of embryogenesis. Its biochemical mechanism is unknown. The proposed studies will provide general insight into the function of this and other HMG Box transcription factors with specific application to a class of human birth defects (46, XY gonadal dysgenesis; """"""""sex reversal""""""""). The proposed studies will test the following propositions: Hypothesis 1. That SRY is a transcription factor, regulating a downstream program that specifies the male phenotype. Hypothesis 2. That SRY exhibits a novel mechanism of DNA recognition and DNA bending. Hypothesis 3. That the DNA-binding properties of SRY are encoded by its HMG box as an autonomous domain. Hypothesis 4. That structure-function relationships may be inferred from analysis of mutations in the SRY HMG box associated with intersex abnormalities of the newborn. This application offers the exciting prospect of applying interdisciplinary methods of biochemistry and molecular biology to a central problem in human sexual development.
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