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Title: Capturing snapshots of APE1 processing DNA damage

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:
 [1] ;  [2] ;  [3] ;  [1] ;  [2]
  1. National Inst. of Environmental Health Sciences (NIEHS), Triangle Park, NC (United States); Univ. of Kansas Medical Center, Kansas City, KS (United States)
  2. National Inst. of Environmental Health Sciences (NIEHS), Triangle Park, NC (United States)
  3. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Publication Date:
OSTI Identifier:
1261477
Grant/Contract Number:
AC05-00OR22725; Z01-ES050158; Z01-ES050161
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
Research Org:
Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); National Institute of Environmental Health Sciences
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES