R964C mutation of DNA polymerase gamma imparts increased stavudine toxicity by decreasing nucleoside analog discrimination and impairing polymerase activity

Antimicrob Agents Chemother. 2009 Jun;53(6):2610-2. doi: 10.1128/AAC.01659-08. Epub 2009 Apr 13.

Abstract

The R964C mutation of human DNA polymerase gamma was recently linked to stavudine (d4T)-mediated mitochondrial toxicity. We utilized pre-steady-state kinetics to determine the effect of this mutation on incorporation of natural substrate dTTP and the active metabolite of d4T (d4TTP). The R964C polymerase gamma holoenzyme demonstrated a 33% decrease in dTTP incorporation efficiency and a threefold-lower d4TTP discrimination relative to that of the wild-type polymerase gamma, providing a mechanistic basis for genetic predisposition to nucleoside reverse transcriptase inhibitor toxicity.

Publication types

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

MeSH terms

  • Anti-HIV Agents / toxicity*
  • DNA Polymerase gamma
  • DNA-Directed DNA Polymerase / chemistry
  • DNA-Directed DNA Polymerase / genetics*
  • DNA-Directed DNA Polymerase / metabolism
  • Humans
  • Mitochondria / drug effects*
  • Mutation*
  • Stavudine / toxicity*
  • Thymine Nucleotides

Substances

  • Anti-HIV Agents
  • Thymine Nucleotides
  • Stavudine
  • DNA Polymerase gamma
  • DNA-Directed DNA Polymerase
  • thymidine 5'-triphosphate