Ultraviolet radiation of DNA causes cell death or skin cancer through formation of cyclobutane pyrimidine dimers (CPD) in the DNA. Many organisms protect their DNA by a light-induced repair mechanism, mediated by DNA photolyase. This extraordinary enzyme restores the genetic information by an electron transfer catalyzed (2+2) cycloreversion of the CPD. Knowledge of the reaction pathways is essential for an understanding of this cancer protection mechanism which is present in many organisms, but probably not in humans. The long term objective of the project is to understand electron transfer catalyzed DNA repair reactions and develop DNA photolyase mimics.
Specific aims i nclude: (i) understand the mechanism of cycloreversion at a molecular level; (ii) obtain the electronic and geometric structures of the molecules and transition states involved; (iii) determine the interactions by which DNA photolyase catalyzes the reaction and (iv) design and synthesize efficient, artificial catalysts with DNA photolyase activity. To reach these goals, the electron transfer catalyzed cycloreversion of the cis,syn and the trans,syn cyclobutane uracil dimer as well as some simple model systems will be investigated. The mechanistic questions will be addressed by a combination of experimental and theoretical methods. The kinetic isotope effects will be determined using a recently developed methodology. The results will be quantitatively interpreted by quantum mechanical calculations, particularly hybrid density functional methods. Interactions of the radical ions with the solvent and enzyme active site will be calculated by cavity and supermolecule approaches. The information obtained will be applied to the design of molecules that selectively bind either cis,syn or the trans,syn CPD by multiple hydrogen bonding and that are covalently attached to photosensitizers. The quantum yields for CPD repair will be optimized by using charged photosensitzers. These studies will increase our knowledge of DNA repair mechanisms and could ultimately lead to drugs to be used for skin cancer prevention.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29CA073775-02
Application #
2837731
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Program Officer
Pelroy, Richard
Project Start
1997-12-01
Project End
2002-11-30
Budget Start
1998-12-01
Budget End
1999-11-30
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Notre Dame
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
824910376
City
Notre Dame
State
IN
Country
United States
Zip Code
46556
Donoghue, Patrick J; Wiest, Olaf (2006) Structure and reactivity of radical ions: new twists on old concepts. Chemistry 12:7018-26