The DNA polymerase gamma R953C mutant is associated with antiretroviral therapy-induced mitochondrial toxicity

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

doi:10.1128/AAC.00976-16

The DNA polymerase gamma R953C mutant is associated with antiretroviral therapy-induced mitochondrial toxicity

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

Biochemistry & Molecular Biology

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

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.

Original language	English (US)
Pages (from-to)	5608-5611
Number of pages	4
Journal	Antimicrobial agents and chemotherapy
Volume	60
Issue number	9
DOIs	https://doi.org/10.1128/AAC.00976-16
State	Published - Sep 1 2016

ASJC Scopus subject areas

Pharmacology
Pharmacology (medical)
Infectious Diseases

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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.",

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T1 - The DNA polymerase gamma R953C mutant is associated with antiretroviral therapy-induced mitochondrial toxicity

AU - Li, Min

AU - Mislak, Andrea C.

AU - Foli, Yram

AU - Agbosu, Esinam

AU - Bose, Vivek

AU - Bhandari, Shreya

AU - Szymanski, Michal R.

AU - Shumate, Christie K.

AU - Yin, Y. Whitney

AU - Anderson, Karen S.

AU - Paintsil, Elijah

PY - 2016/9/1

Y1 - 2016/9/1

N2 - 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.

AB - 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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JO - Antimicrobial agents and chemotherapy

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The DNA polymerase gamma R953C mutant is associated with antiretroviral therapy-induced mitochondrial toxicity

Abstract

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