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

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 nucleot...

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Published inAntimicrobial agents and chemotherapy Vol. 60; no. 9; pp. 5608 - 5611
Main Authors Li, Min, Mislak, Andrea C, Foli, Yram, Agbosu, Esinam, Bose, Vivek, Bhandari, Shreya, Szymanski, Michal R, Shumate, Christie K, Yin, Y Whitney, Anderson, Karen S, Paintsil, Elijah
Format Journal Article
LanguageEnglish
Published United States American Society for Microbiology 01.09.2016
Subjects
Amino Acid Sequence
Anti-Retroviral Agents
Anti-Retroviral Agents - therapeutic use
Antiviral Agents
Binding Sites
DNA Polymerase gamma
DNA-Directed DNA Polymerase
DNA-Directed DNA Polymerase - genetics
Female
HIV Infections - drug therapy
HIV Infections - genetics
Human immunodeficiency virus
Humans
Lentivirus
Male
Middle Aged
Mitochondria
Mitochondria - genetics
Mutation
Mutation - genetics
Protein Conformation
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Summary: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.
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M.L. and A.C.M. contributed equally to this article.
Citation Li M, Mislak AC, Foli Y, Agbosu E, Bose V, Bhandari S, Szymanski MR, Shumate CK, Yin YW, Anderson KS, Paintsil E. 2016. The DNA polymerase gamma R953C mutant is associated with antiretroviral therapy-induced mitochondrial toxicity. Antimicrob Agents Chemother 60:5608–5611. doi:10.1128/AAC.00976-16.
ISSN:0066-4804
1098-6596
DOI:10.1128/AAC.00976-16