Resistance-Guided Mining of Bacterial Genotoxins Defines a Family of DNA Glycosylases
Year: 2022
Type: article
Abstract: produce a diverse number of therapeutic genotoxins, efforts toward targeted discovery of biosynthetic gene clusters (BGCs) producing DNA-damaging agents is lacking. Moreover, work on toxin-resistance genes has lagged behind our understanding of those involved in natural product synthesis. Here, we identified over 70 uncharacterized BGCs producing potentially novel genotoxins through resistance-based genome mining using the azinomycin B-resistance DNA glycosylase AlkZ. We validate our analysis by characterizing the enzymatic activity and cellular resistance of one AlkZ ortholog in the BGC of hedamycin, a potent DNA alkylating agent. Moreover, we uncover a second, phylogenetically distinct family of proteins related to Escherichia coli YcaQ, a DNA glycosylase capable of unhooking interstrand DNA cross-links, which differs from the AlkZ-like family in sequence, genomic location, proximity to BGCs, and substrate specificity. This work defines two families of DNA glycosylase for specialized repair of complex genotoxic natural products and generalized repair of a broad range of alkyl-DNA adducts and provides a framework for targeted discovery of new compounds with therapeutic potential.
Source: mBio
Institutions: Vanderbilt University, Vanderbilt University Medical Center
Language: English
Subfield: Pharmacology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,900
Funders: National Science Foundation, Howard Hughes Medical Institute, Burroughs Wellcome Fund, Vanderbilt University, National Institutes of Health, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Environmental Health Sciences
Awards: Graduate Research Fellowship Program (GRFP), Collaborative Research: RoL: The Evolution of the Genotype-Phenotype Map across Budding Yeasts, G2411831216, DNA Repair Mechanisms of Self-Resistance to Genotoxic Secondary Metabolites, G3729029289, G4659152931, Mechanisms of DNA glycosylase mediated interstrand crosslink repair, Deciphering the phenotypic and genomic traits that underlie the evolution of pathogenicity differences among Aspergillus fumigatus and its close relatives, DIMENSIONS: Collaborative Research: The Making of Biodiversity Across the Yeast Subphylum, Training Program in Environmental Toxicology
OpenAlex ID: W4220882159