DNA repair enzymes are essential for addressing DNA damage that arises continuously in the cell, and these enzymes are central in preventing mutagenesis and cancer that result from this damage. They are also highly upregulated in inflammatory states, and they tend to fail with aging and in neurodegerative diseases. Here I describe the chemical design and application of probes of specific repair enzymes, built from reactive small molecules, designer DNA bases, and synthetic oligonucleotides. These molecules are applied in cells and tissues to probe enzymes that are emerging as important targets in personalized diagnosis, and potentially in treatment, of inflammation, cancer, and neurodegenerative diseases. One example of an enzyme of special interest in this research is OGG1, which recognizes and repairs oxidative damage in DNA. In addition to applications in cells and tissues, I discuss the use of fluorescent enzyme reporters (such as OGR1) in the discovery of novel and potent small-molecule modulators of these repair enzymes. One such compound is SU0268, a 59 nM inhibitor of OGG1. Early results targeting some of these enzymes in cellular and animal models of disease are described.

Molecular probes of DNA repair: Toward new targeted diagnostics and therapies

ACS Spring Meeting 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.