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Capturing Snapshots of APE1 Processing DNA Damage

DNA apurinic-apyrimidinic (AP) sites are prevalent non-coding 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 reactio...

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Autores principales: Freudenthal, Bret D., Beard, William A., Cuneo, Matthew J., Dyrkheeva, Nadezhda S., Wilson, Samuel H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4654669/
https://www.ncbi.nlm.nih.gov/pubmed/26458045
http://dx.doi.org/10.1038/nsmb.3105
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author Freudenthal, Bret D.
Beard, William A.
Cuneo, Matthew J.
Dyrkheeva, Nadezhda S.
Wilson, Samuel H.
author_facet Freudenthal, Bret D.
Beard, William A.
Cuneo, Matthew J.
Dyrkheeva, Nadezhda S.
Wilson, Samuel H.
author_sort Freudenthal, Bret D.
collection PubMed
description DNA apurinic-apyrimidinic (AP) sites are prevalent non-coding 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 due in part to limited structural information. We report multiple high-resolution human APE1:DNA structures that divulge novel features of the APE1 reaction, including the metal binding site, nucleophile, and 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 reveal that APE1 molds the T:G mismatch into a unique Watson-Crick like geometry that distorts the active site 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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spelling pubmed-46546692016-05-01 Capturing Snapshots of APE1 Processing DNA Damage Freudenthal, Bret D. Beard, William A. Cuneo, Matthew J. Dyrkheeva, Nadezhda S. Wilson, Samuel H. Nat Struct Mol Biol Article DNA apurinic-apyrimidinic (AP) sites are prevalent non-coding 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 due in part to limited structural information. We report multiple high-resolution human APE1:DNA structures that divulge novel features of the APE1 reaction, including the metal binding site, nucleophile, and 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 reveal that APE1 molds the T:G mismatch into a unique Watson-Crick like geometry that distorts the active site reducing incision. These snapshots provide mechanistic clarity for APE1, while affording a rational framework to manipulate biological responses to DNA damage. 2015-10-12 2015-11 /pmc/articles/PMC4654669/ /pubmed/26458045 http://dx.doi.org/10.1038/nsmb.3105 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Freudenthal, Bret D.
Beard, William A.
Cuneo, Matthew J.
Dyrkheeva, Nadezhda S.
Wilson, Samuel H.
Capturing Snapshots of APE1 Processing DNA Damage
title Capturing Snapshots of APE1 Processing DNA Damage
title_full Capturing Snapshots of APE1 Processing DNA Damage
title_fullStr Capturing Snapshots of APE1 Processing DNA Damage
title_full_unstemmed Capturing Snapshots of APE1 Processing DNA Damage
title_short Capturing Snapshots of APE1 Processing DNA Damage
title_sort capturing snapshots of ape1 processing dna damage
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4654669/
https://www.ncbi.nlm.nih.gov/pubmed/26458045
http://dx.doi.org/10.1038/nsmb.3105
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