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Edited by Philip C. Hanawalt, Stanford University, Stanford, CA, and approved March 20, 2017 (received for review February 22, 2017)
Significance
DNA glycosylases are important repair enzymes that safeguard the integrity of the genome by excising chemically damaged DNA bases from the phosphoribose backbone. Recently, these enzymes were found to repair DNA interstrand cross-links (ICLs). ICLs are highly toxic DNA lesions formed by various bifunctional metabolites, environmental toxins, and chemotherapeutic agents that block normal DNA metabolism. This work describes the crystal structure of a newly discovered bacterial DNA glycosylase that repairs ICLs formed by azinomycin B, a potent antimicrobial and antitumor agent. The protein belongs to a structural superfamily prevalent in pathogenic bacteria and may serve as an important therapeutic target.
Abstract
DNA glycosylases are important editing enzymes that protect genomic stability by excising chemically modified nucleobases that alter normal DNA metabolism. These enzymes have been known only to initiate base excision repair of small adducts by extrusion from the DNA helix. However, recent reports have described both vertebrate and microbial DNA glycosylases capable of unhooking highly toxic interstrand cross-links (ICLs) and bulky minor groove adducts normally recognized by Fanconi anemia and nucleotide excision repair machinery, although the mechanisms of these activities are unknown. Here we report the crystal structure of Streptomyces sahachiroi 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.
Footnotes
- ↵1To whom correspondence should be addressed: Email: brandt.eichman{at}vanderbilt.edu.
Author contributions: E.A.M. and B.F.E. designed research; E.A.M., G.M.W., and N.P.B. performed research; E.A.M. and B.F.E. analyzed data; and E.A.M. and B.F.E. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The atomic coordinates and structure factors have been deposited in the Protein Data Bank, www.pdb.org (PDB ID code 5UUJ).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1703066114/-/DCSupplemental.
Structure of an ICL DNA glycosylase
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