Essential divalent transition metals such as zinc, copper, and iron play important structural and catalytic roles in over 300 proteins. However, these and other transition metals also pose a potential threat to an organism. Left unchecked these metals can catalyze the generation of free radicals that damage all types of biological molecules. Transition metals must be kept in a physiological window. Diseases like Wilson's disease and Menke's disease demonstrate that either too much or too little metal can lead to pathologies of the liver, kidney, nervous system and connective tissues. Clearly metal homeostasis is an important aspect of cellular function. A major part of this control occurs at the level of transcription. One of the central players in this regulation is the metal response element binding protein (MTF-1). MTF-1 is a sequence specific DNA binding protein that perceives the metal status of a cell and activates genes accordingly. A good deal is known about MTF-1 itself, but very little is known about the protein co-factors that help MTF-1 efficiently activate transcription. We will use an RNAi based screen, in the Drosophila model system, to determine what protein co-factors are required for metal stimulated transcription. In addition we will characterize the physical and functional interactions between MTF-1 and these protein co-factors using a combination of cell based and in vitro assays. Finally we will identify the MTF-1 binding sites across the Drosophila genome to define the MTF-1 regulon that responds to metal stimuli. The long-term objective of our studies is to understand how a cell, in response to a diverse set of metals, differentially regulates the appropriate metal responsive genes to control metal homeostasis.
Humans have a nutritional requirement for essential metals for normal growth and health. But in high doses many of these metals become toxic. Understandably, there is also a need to keep these metals in balance. We are studying the genes that help maintain this equilibrium. The long term goal is to understand how deregulation of these same genes contributes to metal induced disease.
| Denmark, Scott E; Kornfilt, David J P (2017) Catalytic, Enantioselective, Intramolecular Sulfenofunctionalization of Alkenes with Phenols. J Org Chem 82:3192-3222 |
| Marr, Sharon K; Lis, John T; Treisman, Jessica E et al. (2014) The metazoan-specific mediator subunit 26 (Med26) is essential for viability and is found at both active genes and pericentric heterochromatin in Drosophila melanogaster. Mol Cell Biol 34:2710-20 |
| Sims, Hillel I; Chirn, Gung-Wei; Marr 2nd, Michael T (2012) Single nucleotide in the MTF-1 binding site can determine metal-specific transcription activation. Proc Natl Acad Sci U S A 109:16516-21 |
| Marr, Sharon K; Pennington, Katie L; Marr, Michael T (2012) Efficient metal-specific transcription activation by Drosophila MTF-1 requires conserved cysteine residues in the carboxy-terminal domain. Biochim Biophys Acta 1819:902-12 |
