title: The DNA Polymerase Gamma R953C Mutant Is Associated with Antiretroviral Therapy-Induced Mitochondrial Toxicity.
abstract: We found a heterozygous C2857T mutation (R953C) in polymerase gamma (Pol-γ) in an HIV-infected patient with mitochondrial toxicity. The R953C Pol-γ mutant binding affinity for dCTP is 8-fold less than that of the wild type. The R953C mutant shows a 4-fold decrease in discrimination of analog nucleotides relative to the wild type. R953 is located on the "O-helix" that forms the substrate deoxynucleoside triphosphate (dNTP) binding site; the interactions of R953 with E1056 and Y986 may stabilize the O-helix and affect polymerase activity.
authors.affiliation: Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Andrea C
authors.initials: AC
authors.lastname: Mislak
authors.affiliation: Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Yram
authors.initials: Y
authors.lastname: Foli
authors.affiliation: Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Esinam
authors.initials: E
authors.lastname: Agbosu
authors.affiliation: Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Vivek
authors.initials: V
authors.lastname: Bose
authors.affiliation: Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Shreya
authors.initials: S
authors.lastname: Bhandari
authors.affiliation: Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Michal R
authors.initials: MR
authors.lastname: Szymanski
authors.affiliation: Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Christie K
authors.initials: CK
authors.lastname: Shumate
authors.affiliation: Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas, USA ywyin@utmb.edu karen.anderson@yale.edu elijah.paintsil@yale.edu.
authors.forename: Y Whitney
authors.initials: YW
authors.lastname: Yin
authors.affiliation: Department of Pharmacology, Yale School of Medicine, New Haven, Connecticut, USA ywyin@utmb.edu karen.anderson@yale.edu elijah.paintsil@yale.edu.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Anderson
authors.affiliation: Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut, USA Department of Pharmacology, Yale School of Medicine, New Haven, Connecticut, USA Department of Epidemiology & Public Health, Yale School of Medicine, New Haven, Connecticut, USA ywyin@utmb.edu karen.anderson@yale.edu elijah.paintsil@yale.edu.
authors.forename: Elijah
authors.initials: E
authors.lastname: Paintsil
mesh_terms: D000595:Amino Acid Sequence; D044966:Anti-Retroviral Agents / Q000627:therapeutic use*; D001665:Binding Sites; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D011487:Protein Conformation
chemical_list: D044966:Anti-Retroviral Agents; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase