Biomedical Sciences ETDs

Publication Date

Fall 5-13-2017


The phosphodiester backbone of DNA is maintained by DNA ligases. In human cells, there are three genes that encode DNA ligase polypeptides with distinct but overlapping functions. A series of small molecule inhibitors of human DNA ligases were previously identified using a rational structure-based approach. Three of these inhibitors, L82, a DNA ligase I selective inhibitor, and L67, an inhibitor of DNA ligases I and III, and L189, an inhibitor of all three human DNA ligases, have related structures. Here I present and characterize L82-G17 a next-generation ligase I specific inhibitor. L82-G17 is a potent ligase I uncompetitive inhibitor that is shown to act both biochemically and in cell culture models. Furthermore, the binding site for L82 and L82-G17 has been identified via molecular modeling, and verified through mutagenesis.


DNA Ligase, Molecular Modeling, Dissertation, Inhibitor, DNA Repair

Document Type




Degree Name

Biomedical Sciences

Level of Degree


Department Name

Biomedical Sciences Graduate Program

First Committee Member (Chair)

Alan Tomkinson

Second Committee Member

Mary Ann Osley

Third Committee Member

Tudor Oprea

Fourth Committee Member

Montaser Shaheen