Structural basis for processivity and antiviral drug toxicity in human mitochondrial DNA replicase.

ABSTRACT: The human DNA polymerase gamma (Pol ?) is responsible for DNA replication in mitochondria. Pol ? is particularly susceptible to inhibition by dideoxynucleoside-based inhibitors designed to fight viral infection. Here, we report crystal structures of the replicating Pol ?-DNA complex bound to either substrate or zalcitabine, an inhibitor used for HIV reverse transcriptase. The structures reveal that zalcitabine binds to the Pol ? active site almost identically to the substrate dCTP, providing a structural basis for Pol ?-mediated drug toxicity. When compared to the apo form, Pol ? undergoes intra- and inter-subunit conformational changes upon formation of the ternary complex with primer/template DNA and substrate. We also find that the accessory subunit Pol ?B, which lacks intrinsic enzymatic activity and does not contact the primer/template DNA directly, serves as an allosteric regulator of holoenzyme activities. The structures presented here suggest a mechanism for processivity of the holoenzyme and provide a model for understanding the deleterious effects of Pol ? mutations in human disease. Crystal structures of the mitochondrial DNA polymerase, Pol ?, in complex with substrate or antiviral inhibitor zalcitabine provide a basis for understanding Pol ?-mediated drug toxicity.

SUBMITTER: Szymanski MR 

PROVIDER: S-EPMC4547898 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature