Structure of a DNA glycosylase that unhooks interstrand cross-links
Year: 2017
Type: article
Abstract: AlkZ (previously Orf1), a bacterial DNA glycosylase that protects its host by excising ICLs derived from azinomycin B (AZB), a potent antimicrobial and antitumor genotoxin. AlkZ adopts a unique fold in which three tandem winged helix-turn-helix motifs scaffold a positively charged concave surface perfectly shaped for duplex DNA. Through mutational analysis, we identified two glutamine residues and a β-hairpin within this putative DNA-binding cleft that are essential for catalytic activity. Additionally, we present a molecular docking model for how this active site can unhook either or both sides of an AZB ICL, providing a basis for understanding the mechanisms of base excision repair of ICLs. Given the prevalence of this protein fold in pathogenic bacteria, this work also lays the foundation for an emerging role of DNA repair in bacteria-host pathogenesis.
Institution: Vanderbilt University
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: National Science Foundation, U.S. Department of Energy, Vanderbilt University, National Institutes of Health, Office of Science, Michigan Technology Tri-Corridor, National Institute of Environmental Health Sciences, National Center for Research Resources, Office of Extramural Research, National Institutes of Health, Argonne National Laboratory
Awards: G107546177, G1313983767, G1664757510, G1762607292, G1947107004, G2287611682, G262962599, G3075337988, G3329398301, G416541740, A New Structural Architecture for Recognition of DNA Damage, G4773269573, G498139845, G513797252, G5607048534, G5906309288, G5975312287, G6848031779, G6918803902, Crystallographic Automation, G7147508703, G8362364538, Mechanisms of selective excision and oxidative repair of alkylated DNA, Training Program in Environmental Toxicology, G969889393, G993149817
OpenAlex ID: W2606073047