A steric gate prevents mutagenic dATP incorporation opposite 8‐oxo‐deoxyguanosine in mitochondrial DNA polymerases

• DOI: 10.1111/febs.70064
• Publication Date: 2025-03-12T11:21:07Z
• Authors: Noe Baruch‐Torres; Carlos H. Trasviñ...; Alexandru Ionut G...; Upeksha C. Dissan...; Missael Molina‐Ji...; Paola L. García‐M...; Corina Díaz‐Quezada; Tiziana Lodi; G. Andrés Cisneros; Enrico Baruffini; Luis G. Brieba
• Keywords: Deoxyguanosine

Reactive oxygen species (ROS) generate DNA lesions that alter genome integrity. Among those lesions, 7,8‐dihydro‐8‐oxo‐2′‐deoxyguanosine (8‐oxodG) is particularly mutagenic. 8‐oxodG efficiently incorporates deoxycytidine monophosphate (dCMP) and deoxyadenosine (dAMP) via base pairing mediated by its anti syn conformations, respectively. In family‐A polymerases (DNAPs), the amino acids responsible for modulating dCMP or dAMP incorporation across are located in a determined structural position. Those residues conserved tyrosine at N terminus of α‐helix O nonconserved residue six after this tyrosine. yeast mitochondrial DNAP (DNA‐directed polymerase gamma MIP1 [Mip1]), correspond to Y757 F763. We hypothesized phenyl group F763 impinges on conformation 8‐oxodG, therefore reducing misincorporation. Here, we measured using wild‐type Mip1 mutants. Our data suggest both universally assemble steric gate obtrudes 8‐oxodG( ) conformation. As human orthologue Mip1, (HsPolγ) γ, also harbors phenylalanine corresponding position Mip1‐F763, mechanism might similarly be controlling HsPolγ's fidelity when tolerating lesions.