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Capturing snapshots of APE1 processing DNA damage.
Freudenthal, Bret D; Beard, William A; Cuneo, Matthew J; Dyrkheeva, Nadezhda S; Wilson, Samuel H.
Afiliación
  • Freudenthal BD; Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health, Research Triangle Park, USA.
  • Beard WA; Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health, Research Triangle Park, USA.
  • Cuneo MJ; Neutron Sciences Directorate, Oak Ridge National Laboratory, Oak Ridge, Tennessee, USA.
  • Dyrkheeva NS; Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health, Research Triangle Park, USA.
  • Wilson SH; Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health, Research Triangle Park, USA.
Nat Struct Mol Biol ; 22(11): 924-31, 2015 Nov.
Article en En | MEDLINE | ID: mdl-26458045
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Daño del ADN / ADN / ADN-(Sitio Apurínico o Apirimidínico) Liasa / Reparación del ADN Límite: Humans Idioma: En Revista: Nat Struct Mol Biol Asunto de la revista: BIOLOGIA MOLECULAR Año: 2015 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Daño del ADN / ADN / ADN-(Sitio Apurínico o Apirimidínico) Liasa / Reparación del ADN Límite: Humans Idioma: En Revista: Nat Struct Mol Biol Asunto de la revista: BIOLOGIA MOLECULAR Año: 2015 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos