Capturing snapshots of APE1 processing DNA damage
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. Here 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. Moreover, 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. Finally, these snapshots provide mechanistic clarity for APE1 while affording a rational framework to manipulate biological responses to DNA damage.
- Authors:
-
- National Inst. of Environmental Health Sciences (NIEHS), Triangle Park, NC (United States); Univ. of Kansas Medical Center, Kansas City, KS (United States)
- National Inst. of Environmental Health Sciences (NIEHS), Triangle Park, NC (United States)
- Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
- Publication Date:
- Research Org.:
- Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institute of Environmental Health Sciences
- OSTI Identifier:
- 1261477
- Grant/Contract Number:
- AC05-00OR22725; Z01-ES050158; Z01-ES050161
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Nature Structural & Molecular Biology
- Additional Journal Information:
- Journal Volume: 22; Journal Issue: 11; Journal ID: ISSN 1545-9993
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES
Citation Formats
Freudenthal, Bret D., Beard, William A., Cuneo, Matthew J., Dyrkheeva, Nadezhda S., and Wilson, Samuel H. Capturing snapshots of APE1 processing DNA damage. United States: N. p., 2015.
Web. doi:10.1038/nsmb.3105.
Freudenthal, Bret D., Beard, William A., Cuneo, Matthew J., Dyrkheeva, Nadezhda S., & Wilson, Samuel H. Capturing snapshots of APE1 processing DNA damage. United States. https://doi.org/10.1038/nsmb.3105
Freudenthal, Bret D., Beard, William A., Cuneo, Matthew J., Dyrkheeva, Nadezhda S., and Wilson, Samuel H. Mon .
"Capturing snapshots of APE1 processing DNA damage". United States. https://doi.org/10.1038/nsmb.3105. https://www.osti.gov/servlets/purl/1261477.
@article{osti_1261477,
title = {Capturing snapshots of APE1 processing DNA damage},
author = {Freudenthal, Bret D. and Beard, William A. and Cuneo, Matthew J. and Dyrkheeva, Nadezhda S. and Wilson, Samuel H.},
abstractNote = {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. Here 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. Moreover, 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. Finally, these snapshots provide mechanistic clarity for APE1 while affording a rational framework to manipulate biological responses to DNA damage.},
doi = {10.1038/nsmb.3105},
journal = {Nature Structural & Molecular Biology},
number = 11,
volume = 22,
place = {United States},
year = {Mon Oct 12 00:00:00 EDT 2015},
month = {Mon Oct 12 00:00:00 EDT 2015}
}
Web of Science
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Overview of Base Excision Repair Biochemistry
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