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Replication studies of carboxymethylated DNA lesions in human cells.
Wu, Jun; Wang, Pengcheng; Li, Lin; Williams, Nicole L; Ji, Debin; Zahurancik, Walter J; You, Changjun; Wang, Jianshuang; Suo, Zucai; Wang, Yinsheng.
Afiliación
  • Wu J; Department of Chemistry, University of California, Riverside, CA 92521, USA.
  • Wang P; Environmental Toxicology Graduate Program, University of California, Riverside, CA 92521, USA.
  • Li L; Department of Chemistry, University of California, Riverside, CA 92521, USA.
  • Williams NL; Environmental Toxicology Graduate Program, University of California, Riverside, CA 92521, USA.
  • Ji D; Department of Chemistry, University of California, Riverside, CA 92521, USA.
  • Zahurancik WJ; Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USA.
  • You C; Department of Chemistry, University of California, Riverside, CA 92521, USA.
  • Wang J; Department of Chemistry, University of California, Riverside, CA 92521, USA.
  • Suo Z; Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USA.
  • Wang Y; Department of Chemistry, University of California, Riverside, CA 92521, USA.
Nucleic Acids Res ; 45(12): 7276-7284, 2017 Jul 07.
Article en En | MEDLINE | ID: mdl-28531304
Metabolic activation of some N-nitroso compounds (NOCs), an important class of DNA damaging agents, can induce the carboxymethylation of nucleobases in DNA. Very little was previously known about how the carboxymethylated DNA lesions perturb DNA replication in human cells. Here, we investigated the effects of five carboxymethylated DNA lesions, i.e. O6-CMdG, N6-CMdA, N4-CMdC, N3-CMdT and O4-CMdT on the efficiency and fidelity of DNA replication in HEK293T human embryonic kidney cells. We found that, while neither N6-CMdA nor N4-CMdC blocked DNA replication or induced mutations, N3-CMdT, O4-CMdT and O6-CMdG moderately blocked DNA replication and induced substantial frequencies of T→A (81%), T→C (68%) and G→A (6.4%) mutations, respectively. In addition, our results revealed that CRISPR-Cas9-mediated depletion of Pol η resulted in significant drops in bypass efficiencies of N4-CMdC and N3-CMdT. Diminution in bypass efficiencies was also observed for N6-CMdA and O6-CMdG upon depletion of Pol κ, and for O6-CMdG upon removal of Pol ζ. Together, our study provided molecular-level insights into the impacts of the carboxymethylated DNA lesions on DNA replication in human cells, revealed the roles of individual translesion synthesis DNA polymerases in bypassing these lesions, and suggested the contributions of O6-CMdG, N3-CMdT and O4-CMdT to the mutations found in p53 gene of human gastrointestinal cancers.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Timidina / ADN / Desoxiadenosinas / Desoxicitidina / Reparación del ADN / Replicación del ADN Límite: Humans Idioma: En Revista: Nucleic Acids Res Año: 2017 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Timidina / ADN / Desoxiadenosinas / Desoxicitidina / Reparación del ADN / Replicación del ADN Límite: Humans Idioma: En Revista: Nucleic Acids Res Año: 2017 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido