Structural evolution of a DNA repair self-resistance mechanism targeting genotoxic secondary metabolites
Year: 2021
Type: article
Abstract: Microbes produce a broad spectrum of antibiotic natural products, including many DNA-damaging genotoxins. Among the most potent of these are DNA alkylating agents in the spirocyclopropylcyclohexadienone (SCPCHD) family, which includes the duocarmycins, CC-1065, gilvusmycin, and yatakemycin. The yatakemycin biosynthesis cluster in Streptomyces sp. TP-A0356 contains an AlkD-related DNA glycosylase, YtkR2, that serves as a self-resistance mechanism against yatakemycin toxicity. We previously reported that AlkD, which is not present in an SCPCHD producer, provides only limited resistance against yatakemycin. We now show that YtkR2 and C10R5, a previously uncharacterized homolog found in the CC-1065 biosynthetic gene cluster of Streptomyces zelensis, confer far greater resistance against their respective SCPCHD natural products. We identify a structural basis for substrate specificity across gene clusters and show a correlation between in vivo resistance and in vitro enzymatic activity indicating that reduced product affinity-not enhanced substrate recognition-is the evolutionary outcome of selective pressure to provide self-resistance against yatakemycin and CC-1065.
Source: Nature Communications
Language: English
Subfield: Pharmacology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,560
Awards: G102163711, G107546177, G1313983767, G1664757510, G1947107004, G2287611682, DNA Repair Mechanisms of Self-Resistance to Genotoxic Secondary Metabolites, G262962599, G2896567508, G3075337988, G3282013668, G3329398301, G416541740, G4773269573, G498139845, G513797252, G5607048534, G5906309288, G6101244626, G6848031779, G6918803902, G7147508703, A Unique Class of Reductively Activated Oncology Drugs, G8362364538, G969889393, G993149817
OpenAlex ID: W3215597061