DNA Repair Mechanisms of Self-Resistance to Genotoxic Secondary Metabolites

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DNA Repair Mechanisms of Self-Resistance to Genotoxic Secondary MetabolitesBacteria, fungi, and plants produce secondary metabolites that often have antimicrobial properties, making these compounds important in agricultural, industrial, and medical applications. It therefore is important to understand how these compounds exert their toxicity and how the organisms that produce them can avoid self-destruction from toxicity of their own natural products. This research program will benefit society by providing 1) intensive quantitative structural biology experience in the laboratory to trainees at all levels, including postdoctoral, graduate, and undergraduate, 2) hands-on summer research opportunities to undergraduates of Fisk University, a nearby historically black college/university, 3) employment opportunities to women and underrepresented groups, 4) teaching and mentoring opportunities to all trainees, 5) exposure of high school students interested in STEM to biomedical research, and 5) community outreach. The appointment of the Principal Investigator in the College of Arts and Science and the School of Medicine at Vanderbilt University provides an exceptional collaborative and inclusive training environment. This project focuses on the duocarmycin/CC-1065/yatakemycin family of highly toxic natural products from Streptomyces that exhibit potent antimicrobial and antitumor properties by covalently modifying DNA. Recent work from our lab and others has established DNA base excision repair (BER) as a self-resistance mechanism for these and other genotoxic (DNA damaging) natural products. These self-resistance proteins are encoded within the biosynthetic gene clusters involved in synthesis and regulation of the natural products. While most work on biosynthetic gene clusters has focused on the enzymes that synthesize the natural product, the roles of the non-synthesis proteins, including those involved in self-resistance to toxicity, have lagged behind. The long-term goals of this project are to understand the roles of these self-protection mechanisms, which can lead to discovery of novel biological and biochemical mechanisms of the enzymes involved, and to increased yield of the natural product from a re-engineered producing organism. The short-term goal is to understand the specialized BER mechanism of duocarmycin/CC-1065/yatakemycin resistance in Streptomyces. Structural biology, biochemistry, genetics, and cell biology will be used to characterize the basis for toxicity of each compound and the specificity and mechanisms of the unique DNA glycosylases and apurinic endonucleases that catalyze the first two steps in BER of this important family of natural products.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.