Adam Thelen

Ph.D. Student

Areas of Interest

Mentor:  Dr. Patrick O'Brien

Clinical Interests

DNA damage is an unavoidable challenge of cellular life.  The base excision repair (BER) pathway, present in all domains of life, is tasked with removing diverse single-base DNA lesions and incorporating new nucleotides to properly complement the opposing strand.  Glycosylase family enzymes catalyze the first step of BER, wherein a lesion is detected and the damaged base is cleaved at the N-glycosidic bond to create an abasic site.  This is typically accomplished through a base-flipping mechanism which rotates the target base out of the DNA helix and into the enzyme active site for cleavage.  The human alkyladenine DNA glycosylase (AAG) acts by such a mechanism, and it excises a broad range of substrates including common methyl and etheno purine adducts.  Despite the enzyme’s known role excising lesions such as 1,N6-ethenoadenine, N3-methyladenine, N7-methylguanine, and hypoxanthine, its full substrate range remains unclear.  Likewise, the structural features of the enzyme’s active site which allow it to identify and excise such a wide spectrum of lesions have yet to be characterized.  My project focuses on using transient and steady state enzyme kinetics to learn more about the substrate specificity of AAG.