The Chemistry of Life Processes Program in the Division of Chemistry is funding Steven Rokita of Johns Hopkins University for research aimed at increasing our understanding of the way in which our cells react to toxins in the environment. In particular, the investigators are looking at how cells repair damage those toxins might inflict. One way the damage occurs is through a process known as DNA alkylation, in which small chemical groups are added to the molecules that make up genes. Food preservatives, natural flavorings and even drugs can induce DNA alkylation. The current project is designed to assess the biochemical consequences of toxins that interact reversibly with DNA. The reversibility of the deleterious interactions between these molecules and DNA creates the possibility that the effects of the toxins are amplified and may overwhelm the repair capacity of cells. To study the process in detail and identify the most dramatic effects of the reversibility, a series of model compounds is being prepared and tested for each step of the DNA repair mechanism. This work is having a broader impact on scientist's ability to evaluate the toxicology of substances prior to their market release. It is having a further impact on the training of the next generation of scientists, both undergraduate and graduate students, by encouraging them to recognize and pursue problems that transcend the traditional barriers between organic chemistry and biochemistry and are important for the human health.

In this project, the structural determinants required for efficient diffusion of covalent cross-linking within duplex DNA are being identified. This is being accomplished through the synthesis and evaluation of quinone methide intermediates that express a range of reaction kinetics and DNA affinities. The principles gleaned from this first activity will be used for challenging enzymes responsible for DNA repair with reversible and dynamic cross-links. The entities formed during each step of cross-link repair will be mapped by diagnostic fragmentation and separation using electrophoresis and chromatography. Initial attention will be directed to isolated DNA and then progress to nucleosomes and finally embrace the complexity of crude cell extracts.

Agency
National Science Foundation (NSF)
Institute
Division of Chemistry (CHE)
Type
Standard Grant (Standard)
Application #
1405123
Program Officer
Max Funk
Project Start
Project End
Budget Start
2014-08-15
Budget End
2018-07-31
Support Year
Fiscal Year
2014
Total Cost
$459,486
Indirect Cost
Name
Johns Hopkins University
Department
Type
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21218