scholarly journals Mitochondrial DNA polymerase-γ and human disease

2006 ◽  
Vol 15 (suppl_2) ◽  
pp. R244-R252 ◽  
Author(s):  
Gavin Hudson ◽  
Patrick F. Chinnery
Keyword(s):  
Mitochondrial Dna ◽  
Dna Polymerase ◽  
Human Disease ◽  
Mitochondrial Dna Polymerase ◽  
Dna Polymerase Γ

Genomic Structure of Murine Mitochondrial DNA Polymerase-γ

2000 ◽  
Vol 19 (10) ◽  
pp. 601-605 ◽  
Author(s):  
Justin L. Mott ◽  
Grace Denniger ◽  
Steve J. Zullo ◽  
H. Peter Zassenhaus
Keyword(s):  
Mitochondrial Dna ◽  
Dna Polymerase ◽  
Genomic Structure ◽  
Mitochondrial Dna Polymerase ◽  
Dna Polymerase Γ

scholarly journals Functional Human Mitochondrial DNA Polymerase γ Forms a Heterotrimer

2005 ◽  
Vol 281 (1) ◽  
pp. 374-382 ◽  
Author(s):  
Elena Yakubovskaya ◽  
Zhixin Chen ◽  
José A. Carrodeguas ◽  
Caroline Kisker ◽  
Daniel F. Bogenhagen
Keyword(s):  
Mitochondrial Dna ◽  
Dna Polymerase ◽  
Human Mitochondrial Dna ◽  
Mitochondrial Dna Polymerase ◽  
Dna Polymerase Γ

scholarly journals Acute and Delayed Toxicity Studies on the Antiherpesvirus Agents 5-Methoxymethyl-2′-Deoxycytidine and 5-Methoxymethyl-2′-Deoxyuridine

1997 ◽  
Vol 8 (5) ◽  
pp. 439-442
Author(s):  
R Shi ◽  
SV Gupta ◽  
M Kukhanova ◽  
SVP Kumar ◽  
AL Stuart ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Dna Polymerase ◽  
Doubling Time ◽  
Prolonged Exposure ◽  
Potent Inhibitor ◽  
Control Drug ◽  
Delayed Toxicity ◽  
Simplex Virus ◽  
Mitochondrial Dna Polymerase ◽  
Dna Polymerase Γ

5-Methoxymethyl-2′-deoxycytidine (MMdCyd) and the corresponding deoxyuridine analogue, 5-methoxymethyl-2′-deoxyuridine (MMdUrd) are selective antiherpesvirus agents. MMdCyd (ED50 1.5 μM) is a more potent inhibitor of herpes simplex virus replication than MMdUrd (ED50 30 μM) when maintained in the deoxycytidine form (deamination prevented). The 5′-triphos-phates, MMdCTP and MMdUTP, were synthesized, and incorporation into DNA by mitochondrial DNA polymerase γ was investigated. MMdCTP and MMdUTP were incorporated into DNA in place of dCTP and dTTP, respectively. The effect of MMdCyd and MMdUrd on cell growth (acute toxicity) and prolonged exposure (delayed cytotoxicity) in CEM cells was investigated. The two analogues did not exhibit acute or delayed toxicity (2 weeks exposure) up to 1000 μM. In contrast, at a concentration as low as 0.125 μM of 2′,3′-dideoxycytidine (ddC; control drug), the doubling time of the cells increased after 10 days. At higher concentrations, a very marked increase in doubling time was observed from 6 days onward with ddC treatment. The data suggest that in uninfected cells neither MMdUrd nor MMdCyd are anabolized to the triphosphate form in significant amounts. As a result, little or no MMdCTP or MMdUTP builds up in the mitochondria and thus delayed toxicity is not observed.

scholarly journals Synergistic Effects of thein cisT251I and P587L Mitochondrial DNA Polymerase γ Disease Mutations

2017 ◽  
Vol 292 (10) ◽  
pp. 4198-4209 ◽  
Author(s):  
Karen L. DeBalsi ◽  
Matthew J. Longley ◽  
Kirsten E. Hoff ◽  
William C. Copeland
Keyword(s):  
Mitochondrial Dna ◽  
Dna Polymerase ◽  
Synergistic Effects ◽  
Disease Mutations ◽  
Mitochondrial Dna Polymerase ◽  
Dna Polymerase Γ

scholarly journals Atomistic Molecular Dynamics Simulations of Mitochondrial DNA Polymerase γ: Novel Mechanisms of Function and Pathogenesis

Biochemistry ◽  
2017 ◽  
Vol 56 (9) ◽  
pp. 1227-1238 ◽  
Author(s):  
Liliya Euro ◽  
Outi Haapanen ◽  
Tomasz Róg ◽  
Ilpo Vattulainen ◽  
Anu Suomalainen ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Mitochondrial Dna ◽  
Molecular Dynamics Simulations ◽  
Dna Polymerase ◽  
Dynamics Simulations ◽  
Mitochondrial Dna Polymerase ◽  
Dna Polymerase Γ

scholarly journals Sensitive Assay for Mitochondrial DNA Polymerase γ

1999 ◽  
Vol 45 (10) ◽  
pp. 1725-1733 ◽  
Author(s):  
Robert K Naviaux ◽  
David Markusic ◽  
Bruce A Barshop ◽  
William L Nyhan ◽  
Richard H Haas
Keyword(s):  
Mitochondrial Dna ◽  
Dna Polymerase ◽  
Dynamic Range ◽  
Mitochondrial Protein ◽  
Reaction Products ◽  
Clinical Assay ◽  
Mitochondrial Dna Depletion ◽  
Mitochondrial Dna Polymerase ◽  
Muscle Biopsies ◽  
Dna Polymerase Γ

Abstract Background: The mitochondrial DNA polymerase γ is the principal polymerase required for mitochondrial DNA replication. Primary or secondary deficiencies in the activity of DNA polymerase γ may lead to mitochondrial DNA depletion. We describe a sensitive and robust clinical assay for this enzyme. Methods: The assay was performed on mitochondria isolated from skeletal muscle biopsies. High-molecular weight polynucleotide reaction products were captured on ion-exchange paper, examined qualitatively by autoradiography, and quantified by scintillation counting. Results: Kinetic analysis of DNA polymerase γ by this method showed a Km for dTTP of 1.43 μmol/L and a Ki for azidothymidine triphosphate of 0.861 μmol/L. The assay was linear from 0.1 to 2 μg of mitochondrial protein. The detection limit was 30 units (30 fmol dTMP incorporated in 30 min). The linear dynamic range was three orders of magnitude; 30–30 000 units. Imprecision (CV) was 6.4% within day and 12% between days. Application of this assay to a mixed population of 38 patients referred for evaluation of mitochondrial disease revealed a distribution with a range of 0–2506 U/μg, reflecting extensive biologic variation among patients with neuromuscular disease. Conclusion: This assay provides a useful adjunct to current laboratory methods for the evaluation of patients with suspected mitochondrial DNA depletion syndromes.

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