Bulky Lesion Bypass Requires Dpo4 Binding in Distinct Conformations.

Liyanage, Pramodha S; Walker, Alice R; Brenlla, Alfonso; Cisneros, G Andrés; Romano, Louis J; Rueda, David

Liyanage, Pramodha S; Walker, Alice R; Brenlla, Alfonso; Cisneros, G Andrés; Romano, Louis J; Rueda, David.

Afiliación

Liyanage PS; Department of Chemistry, Wayne State University, Detroit, MI, 48202, USA.
Walker AR; Department of Chemistry, University of North Texas, Denton, TX, 76201, USA.
Brenlla A; Department of Chemistry, Wayne State University, Detroit, MI, 48202, USA.
Cisneros GA; Department of Chemistry, University of North Texas, Denton, TX, 76201, USA.
Romano LJ; Department of Chemistry, Wayne State University, Detroit, MI, 48202, USA. ljr@chem.wayne.edu.
Rueda D; Molecular Virology, Department of Medicine, Imperial College London, Du Cane Road, London, W12 0NN, UK. david.rueda@imperial.ac.uk.

Sci Rep ; 7(1): 17383, 2017 12 12.

Article en En | MEDLINE | ID: mdl-29234107

RESUMEN

Translesion DNA synthesis is an essential process that helps resume DNA replication at forks stalled near bulky adducts on the DNA. Benzo[a]pyrene (B[a]P) is a polycyclic aromatic hydrocarbon (PAH) that can be metabolically activated to benzo[a]pyrene diol epoxide (BPDE), which then can react with DNA to form carcinogenic DNA adducts. Here, we have used single-molecule florescence resonance energy transfer (smFRET) experiments, classical molecular dynamics simulations, and nucleotide incorporation assays to investigate the mechanism by which the model Y-family polymerase, Dpo4, bypasses a (+)-cis-B[a]P-N 2-dG adduct in DNA. Our data show that when (+)-cis-B[a]P-N 2-dG is the templating base, the B[a]P moiety is in a non-solvent exposed conformation stacked within the DNA helix, where it effectively blocks nucleotide incorporation across the adduct by Dpo4. However, when the media contains a small amount of dimethyl sulfoxide (DMSO), the adduct is able to move to a solvent-exposed conformation, which enables error-prone DNA replication past the adduct. When the primer terminates across from the adduct position, the addition of DMSO leads to the formation of an insertion complex capable of accurate nucleotide incorporation.

Asunto(s)

Benzo(a)pireno/metabolismo; Aductos de ADN/metabolismo; Reparación del ADN; ADN Polimerasa Dirigida por ADN/metabolismo; Simulación de Dinámica Molecular; Sulfolobus solfataricus/enzimología; Enzimas Reparadoras del ADN/metabolismo; Replicación del ADN

Texto completo

Añadir a Mi BVS

Imprimir

XML

PubMed Links

Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Benzo(a)pireno / Aductos de ADN / Sulfolobus solfataricus / ADN Polimerasa Dirigida por ADN / Reparación del ADN / Simulación de Dinámica Molecular Idioma: En Revista: Sci Rep Año: 2017 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido

Texto completo

Añadir a Mi BVS

Imprimir

XML

PubMed Links

Buscar en Google