Grant: Discovery Grants Program - Individual

Deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) are the central molecules of life. The discovery of the double helix structure of DNA, described by Watson and Crick over 60 years ago, continues to lead to numerous advances in biology and medicine. More recently, this elegant structure and the nature of its specific interactions have inspired scientists and engineers to investigate technological applications for nucleic acids. Through organic synthesis, modification of the nucleic acid scaffold can be achieved leading to molecules with increased functionality for a broad range of applications that can improve our society. One avenue of nucleic acid based research that our group will explore involves investigation of the relationship between modification/damage to the information content of DNA with the response of DNA repair proteins. The importance of DNA repair was endorsed by the scientific community with the 2015 Nobel Prize in Chemistry awarded to Lindahl, Modrich and Sancar for their contributions to our understanding of DNA repair pathways. Our laboratory has been interested in exploring the ability of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT) to act upon on a variety of modified nucleic acid structures prepared by organic synthesis. AGTs can remove alkylation damage from the O6-atom of 2'-deoxyguanosine and O4-atom of thymidine with differences in repair efficiency towards these lesions depending on the source of the AGT (i.e. Human versus E. coli). To address this issue, we will explore the influence of various groups at the C5-position of thymidine on AGT repair. We will also explore AGT repair of intrastrand cross-link lesions in G-quadruplex structures. These findings will enhance our knowledge of substrates that AGT, a protein important for health and growing applications in biotechnology, can process. Our group will study the processing of DNA damage by bypass polymerases with chemically synthesized analogs of DNA damage resulting from reactive nitrogen species and investigate the influence of nucleobase orientation on nucleotide incoportation. Understanding the mechanisms by which these proteins bypass damage provides important insights explaining why some forms of damage offer such a challenge for the cell to repair. We will study ways to stabilize the parallel stranded duplex formed by polyadenosine, a structure that is of interest for applications in nucleic acid nanoscience. Also, we will develop methods for incorporation of selenium into nucleic acids to add to the toolbox of methods for structure determination by X-ray crystallography. Canada has a very active and growing research community in the field of nucleic acid chemistry. This research program will provide multidisciplinary training in the fields of organic chemistry and biochemistry to the next generation of scientists embarking in this important field of science.