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Capturing snapshots of APE1 processing DNA damage

Nature Structural & Molecular Biology volume 22, pages 924–931 (2015)Cite this article

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Abstract

DNA apurinic-apyrimidinic (AP) sites are prevalent noncoding threats to genomic stability and are processed by AP endonuclease 1 (APE1). APE1 incises the AP-site phosphodiester backbone, generating a DNA-repair intermediate that is potentially cytotoxic. The molecular events of the incision reaction remain elusive, owing in part to limited structural information. We report multiple high-resolution human APE1–DNA structures that divulge new features of the APE1 reaction, including the metal-binding site, the nucleophile and the arginine clamps that mediate product release. We also report APE1–DNA structures with a T-G mismatch 5′ to the AP site, representing a clustered lesion occurring in methylated CpG dinucleotides. These structures reveal that APE1 molds the T-G mismatch into a unique Watson-Crick-like geometry that distorts the active site, thus reducing incision. These snapshots provide mechanistic clarity for APE1 while affording a rational framework to manipulate biological responses to DNA damage.

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Figure 1: High-resolution APE1–DNA product complex.
Figure 2: Swinging of R181 facilitates product stability.
Figure 3: R177 intercalates into the major groove anchoring the orphan base.
Figure 4: High resolution APE1–DNA substrate complex.
Figure 5: APE1 E96Q D210N mismatch substrate complex.
Figure 6: APE1 T-G mismatch product complex.
Figure 7: APE1 mechanism during strand cleavage.

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Acknowledgements

We thank the Collaborative Crystallography group at NIEHS for help with data collection and analysis. We thank L. Pedersen and L. Perera for valuable discussions. This research was supported in part by the Intramural Research Program of the US National Institutes of Health, National Institute of Environmental Health Sciences (project numbers Z01-ES050158 and Z01-ES050161 (S.H.W.)). A part of this research was performed at Oak Ridge National Laboratory's Spallation Neutron Source and the Joint Institute for Neutron Sciences Biophysical Characterization Laboratory, sponsored by the United States Department of Energy, Office of Basic Energy Sciences (M.J.C.). N.S.D is supported in part by Eli Lilly and Co. and the United States Department of State, as part of the United States-Russia Collaboration in the Biomedical Sciences US National Institutes of Health Visiting Fellows Program.

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  1. Bret D Freudenthal & Nadezhda S Dyrkheeva

    Present address: Present addresses: Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas, USA (B.D.F.) and Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Science, Novosibirsk, Russia (N.S.D.).,

Authors and Affiliations

  1. Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health, Research Triangle Park, USA

    Bret D Freudenthal, William A Beard, Nadezhda S Dyrkheeva & Samuel H Wilson

  2. Neutron Sciences Directorate, Oak Ridge National Laboratory, Oak Ridge, Tennessee, USA

    Matthew J Cuneo

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Contributions

B.D.F. designed the project. B.D.F. carried out crystallography. N.S.D. did the kinetic analyses. M.J.C. did the binding studies. B.D.F., W.A.B. and S.H.W. prepared the manuscript. All authors discussed the results and commented on the manuscript.

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Integrated supplementary information

Supplementary Figure 1 Overlay of APE1–DNA product complexes.

(a) An overlay of the previous (PDB ID 4IEM) (Tsutakawa, S.E. et al., J. Biol. Chem. 288, 8445-8455, 2013) APE1:DNA product complex and our high-resolution product complex shown in yellow and green, respectively. (b) A focused view on the DNA from the overlay in panel (a). The only major difference in the DNA conformer is indicated with a red arrow. The end of the DNA from the previous structure folds back and stacks with the orphan base pair. This is not observed with longer 21-mers employed in the current study.

Supplementary Figure 2 The chiral 2′-O-methyl phosphorothioate species.

(a) An omit map contoured at 3σ is shown in green. The THF moiety and 5´-flanking 2´O-methyl phosphorothioate (2´-OMe(PS)) are shown in stick format. (b) The Sp and Rp chiral species are shown. The shift of the Rp species is indicated with a black arrow.

Supplementary Figure 3 APE1 substrate complex with metal bound.

(a) Close-up view of the metal binding site in the APE1:DNA substrate complex with Mn2+ shown as a purple sphere. The anomalous density map is shown in purple contoured at 5σ. The coordinating water molecules are shown as blue spheres and side chains in stick format. The cleavage point is indicated (black arrow). (b) Overlay of the metal bound and metal free substrate complex is shown in green and salmon, respectively. The Mn2+ ion is shown as a purple sphere. Shifts (Å) in side chain residues following metal binding are highlighted by a red arrow. (c) Overlay of the metal bound substrate and product complexes are shown in green and yellow, respectively. Mg2+ and Mn2+ are shown as red and purple spheres respectively. The shift (Å) in the metal ion from the substrate to product binding site is indicated by a red arrow.

Supplementary Figure 4 The E96Q D210N APE1 mismatch substrate complex.

(a) An omit map contoured at 3σ is shown for key active site residues and the nucleophilic water. (b) Overlay of the APE1 substrate complex obtained with modified DNA and wild-type enzyme (green) or using natural DNA and the E96Q D210N double mutant (cyan). The nucleophilic water and amino acids D210, N68, and E96 are shown for each structure. The hydrogen bonding interaction for the E96Q D210N mutant protein is shown with dashes. The metal binding site is indicated with a black circle.

Supplementary Figure 5 Overlay of metal-bound APE1 structures.

Overlay of our APE1:DNA substrate structure determined in the presence of Mn2+ with the apoenzyme APE1 structure determined in the presence of (a) manganese (PDB ID 4QH9) (He, H., Chen, Q. & Georgiadis, M.M., Biochemistry 53, 6520-6529, 2014) or (b) lead (PDB ID 1E9N) (Beernink, P.T. et al., J. Mol. Biol. 307, 1023-1034, 2001). The DNA is shown in grey and protein in green for our substrate structure. The manganese and water ions from our APE1:DNA complex are shown as dark purple and blue spheres, respectively. The dashes correspond to key active site contacts in our APE1:DNA complex. Only the Mn2+ ion is shown as magenta for the apoenzyme in panel (a). In panel (b) only the lead ions, in site A and B, are shown as black spheres for the apoenzyme APE1 structure.

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Freudenthal, B., Beard, W., Cuneo, M. et al. Capturing snapshots of APE1 processing DNA damage. Nat Struct Mol Biol 22, 924–931 (2015). https://doi.org/10.1038/nsmb.3105

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