CAREER: Iron Substitution and Oxidative Damage in Zinc Finger Proteins

University Of Maryland At Baltimore, Baltimore

Investigators

Abstract

This CAREER award in the Inorganic, Bioinorganic and Organometallic Chemistry program supports research by Professor Sarah L. Michel at the University of Maryland Baltimore County (UMBC) to determine the consequences of iron substitution in zinc finger proteins. Iron has the potential to substitute for zinc in the metal binding sites of zinc finger proteins; however, this substitution may leave the zinc finger protein susceptible to oxidative damage. The proposed studies are aimed at unraveling the bioinorganic chemistry of iron substitution in zinc binding domains and the susceptibility of zinc finger proteins, with either zinc or iron coordinated, to oxidation. Two specific zinc finger proteins will be examined: tristetraprolin (TTP), an RNA-binding Cys3His-M(II) protein, and Neural Zinc Finger Factor 1 (NZF1), a DNA-binding Cys2HisCys-M(II) protein. The research aims to: 1) determine and quantify the factors that control the molecular recognition events between ferric and ferrous iron-substituted TTP and NZF1 and their RNA/DNA targets and 2) characterize the pathway of oxidative damage for iron substituted TTP and NZF1 and compare to the zinc bound and apo forms of the proteins. An educational/research partnership between the pharmaceutical sciences department (PSC) at UMBC and the chemistry department at Morgan State University (MSU), a historically black college or university (HBCU) in Baltimore City will be developed. Undergraduates from MSU will participate in a week-long graduate school immersion program, SIMSI, that includes mentoring by PSC graduate students, a "Mini-Grad" school experience, skills building workshops and a career opportunities forum. MSU undergraduates will also participate in summer research experiences, online discussion groups with PSC mentors, and PSC department seminars. A DVD describing the partnership will be produced and made available to faculty at peer institutions. The aim of this partnership is to inspire undergraduate students from under-represented groups to pursue science careers by providing short and long term research experiences coupled with mentoring. PSC graduate students from the PI's laboratory will be involved in the partnership, and the group's work on iron substitution in zinc finger proteins will be the focus of one of the "Mini-Grad" school projects performed by MSU undergraduates. An ongoing research collaboration between Dr. Cymet at MSU and undergraduate students in her laboratory will enhance both the training of Dr. Cymet and her students but also the training of Dr. Michel's students. Undergraduate and graduate students working on the iron-zinc finger project will receive broad training in research at the interface of inorganic chemistry and biology.