Grant: Discovery Grants Program - Individual

The ultimate goal of the proposed research is to understand how DNA is damaged and repaired in our bodies. The genetic information contained in our DNA can be damaged by exposure to external and internal influences (e.g., UV light, pollutants and hormones). Although enzymes in our cells can repair this damage, some damage persists and has significant health effects (e.g., cancer, inflammatory diseases and autoimmune disorders). The short-term goal of the proposed work is to use computational chemistry to decipher the details of specific DNA damage and repair pathways. Highly accurate computer calculations can serve as powerful predictors of experimental outcomes, clarify discrepancies between experimental hypotheses and results, and provide information not available from traditional wet' experiments. The proposed research is uniquely based on the judicious use of a range of computational approaches and close consultations with leading experimentalists. First, the proposed work will focus on DNA adducts formed when carcinogens arising from many sources (pesticides, tobacco, petroleum) directly interact with DNA. These adducts have been linked to several cancers and other diseases. The proposed research will provide currently missing structure-outcome relationships that are necessary to direct future studies geared towards combating the effects of DNA adducts. Specifically, calculations will map how chemical composition affects adduct formation pathways and cellular processing, including copying DNA for cell division (DNA replication) and synthesis of proteins (DNA transcription). Second, the proposed research will address currently unanswered questions about the speed (catalytic efficiency) and type of damage repaired (selectivity) by enzymes involved in two key DNA repair processes, namely nucleotide (NER) and base (BER) excision repair. Initially, interactions between damaged DNA and repair enzymes will be modeled to reveal structural features that are critical for identifying DNA damage. Subsequently, advanced techniques will be used to understand the chemical steps employed by many enzymes in each repair process. Studying DNA damage and repair is exceedingly important due to our increased exposure to harmful agents in the environment. Despite the necessity of calculations to complement and interpret experimental data, which often lack direct structural details or are time prohibitive to collect, the use of computational modeling in this field is limited. The proposed research will have immediate impact in chemistry and biology, as underscored by the award of the 2015 Nobel Prize in Chemistry to those who identified key DNA repair pathways. In the longer term, the proposed work will uncover new chemistry that will aid the development of novel diagnostic assays or drugs to combat human diseases, or the design of innovative materials based on modified DNA structures.