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

• DOI: 10.1128/aac.00976-16
• Publication Date: 2016-07-06T02:58:59Z
• Authors: Min Li; Andrea C. Mislak; Yram Foli; Esinam Agbosu; Vivek Bose; Shreya Bhandari; Michal R. Szymanski; Christie K. Shumate; Y. Whitney Yin; Karen S. Anderson; Elijah Paintsil
• Keywords: Male; 0303 health sciences; Binding Sites; Protein Conformation; HIV Infections; DNA-Directed DNA Polymerase; Middle Aged; DNA Polymerase gamma; Mitochondria; 3. Good health; 03 medical and health sciences; Anti-Retroviral Agents; Mutation; Humans; Female; Amino Acid Sequence

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.