A steric gate prevents mutagenic dATP incorporation opposite 8-oxo-deoxyguanosine in mitochondrial DNA polymerases
Artículo
Te invitamos a leer el artículo "A steric gate prevents mutagenic dATP incorporation opposite 8-oxo-deoxyguanosine in mitochondrial DNA polymerases" publicado en FEBS Journal, a cargo del profesor investigador de la Unidad de Genómica Avanzada del Cinvestav Dr. Luis Gabriel Brieba de Castro, Profesor Investigador de la UGA.
Autores: Noe Baruch-Torres / Carlos H. Trasviña-Arenas / Alexandru Ionut Gilea/ Upeksha C. Dissanayake/ Missael Molina Jiménez/ Paola L. García-Medel / Corina Díaz-Quezada / Tiziana Lodi G / Andrés Cisneros / Enrico Baruffini / Luis G. Brieba
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Unidad de Genómica Avanzada, Centro de Investigación y de Estudios Avanzados (Cinvestav), Irapuato, Mexico
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Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA
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Sealy Center for Structural Biology and Molecular Biophysics, Galveston, TX, USA
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Centro de Investigación sobre el Envejecimiento, Centro de Investigación y de Estudios Avanzados (Cinvestav) Unidad Sede Sur, Mexico City, Mexico
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Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Italy
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Department of Chemistry and Biochemistry, University of Texas at Dallas, Richardson, TX, USA
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Department of Physics, University of Texas at Dallas, Richardson, TX, USA
Felicitamos al estudiantado y profesorado que contribuyeron en esta investigación por su arduo trabajo.
Summary:
Reactive oxygen species (ROS) generate DNA lesions that alter genome integrity. Among those DNA lesions, 7,8-dihydro-8-oxo-2′-deoxyguanosine (8-oxodG) is particularly mutagenic. 8-oxodG efficiently incorporates deoxycytidine monophosphate (dCMP) and deoxyadenosine monophosphate (dAMP) via base pairing mediated by its anti and syn conformations, respectively. In family-A DNA polymerases (DNAPs), the amino acids responsible for modulating dCMP or dAMP incorporation across 8-oxodG are located in a determined structural position. Those residues are a conserved tyrosine located at the N terminus of the α-helix O and a nonconserved residue located six amino acids after this conserved tyrosine. In yeast mitochondrial DNAP (DNA-directed DNA polymerase gamma MIP1 [Mip1]), those residues correspond to amino acids Y757 and F763. We hypothesized that the phenyl group of the F763 residue impinges on the syn conformation of 8-oxodG, therefore reducing dAMP misincorporation. Here, we measured dCMP and dAMP incorporation across 8-oxodG using wild-type and F763 Mip1 mutants. Our data suggest that both residue F763 and the universally conserved Y757 assemble a steric gate that obtrudes the 8-oxodG(syn) conformation. As the human orthologue of Mip1, DNA polymerase gamma (HsPolγ) or DNAP γ, also harbors phenylalanine at the corresponding position to Mip1-F763, the steric gate mechanism might similarly be responsible for controlling HsPolγ's fidelity when tolerating 8-oxodG lesions.