The DNA Polymerase Gamma R953C Mutant Is Associated with Antiretroviral Therapy-Induced Mitochondrial Toxicity

Antimicrob Agents Chemother. 2016 Aug 22;60(9):5608-11. doi: 10.1128/AAC.00976-16. Print 2016 Sep.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Anti-Retroviral Agents / therapeutic use*
  • Binding Sites
  • DNA Polymerase gamma
  • DNA-Directed DNA Polymerase / genetics*
  • Female
  • HIV Infections / drug therapy
  • HIV Infections / genetics
  • Humans
  • Male
  • Middle Aged
  • Mitochondria / genetics*
  • Mutation / genetics*
  • Protein Conformation

Substances

  • Anti-Retroviral Agents
  • DNA Polymerase gamma
  • DNA-Directed DNA Polymerase