A Mechanistic View of Human Mitochondrial DNA Polymerase Gamma: Providing Insight into Drug Toxicity and Mitochondrial Disease

Overview

Journal Biochim Biophys Acta

Specialties Biochemistry
Biophysics

Date 2010 Jan 20

PMID 20083238

Citations 11

Authors

Christopher M Bailey

Karen S Anderson

Affiliations

Soon will be listed here.

Abstract

Mitochondrial DNA polymerase gamma (Pol gamma) is the sole polymerase responsible for replication of the mitochondrial genome. The study of human Pol gamma is of key importance to clinically relevant issues such as nucleoside analog toxicity and mitochondrial disorders such as progressive external ophthalmoplegia. The development of a recombinant form of the human Pol gamma holoenzyme provided an essential tool in understanding the mechanism of these clinically relevant phenomena using kinetic methodologies. This review will provide a brief history on the discovery and characterization of human mitochondrial DNA polymerase gamma, focusing on kinetic analyses of the polymerase and mechanistic data illustrating structure-function relationships to explain drug toxicity and mitochondrial disease.

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References

Zeviani M, Bresolin N, Gellera C, Bordoni A, Pannacci M, Amati P . Nucleus-driven multiple large-scale deletions of the human mitochondrial genome: a new autosomal dominant disease. Am J Hum Genet. 1990; 47(6):904-14. PMC: 1683915. View

Lee H, Johnson K . Fidelity of the human mitochondrial DNA polymerase. J Biol Chem. 2006; 281(47):36236-40. DOI: 10.1074/jbc.M607964200. View

Yarchoan R, Mitsuya H, Myers C, Broder S . Clinical pharmacology of 3'-azido-2',3'-dideoxythymidine (zidovudine) and related dideoxynucleosides. N Engl J Med. 1989; 321(11):726-38. DOI: 10.1056/NEJM198909143211106. View

Feng J, Shi J, Schinazi R, Anderson K . Mechanistic studies show that (-)-FTC-TP is a better inhibitor of HIV-1 reverse transcriptase than 3TC-TP. FASEB J. 1999; 13(12):1511-7. DOI: 10.1096/fasebj.13.12.1511. View

GEUSKENS M, Hardt N, Pedrali-Noy G, Spadari S . An autoradiographic demonstration of nuclear DNA replication by DNA polymerase alpha and of mitochondrial DNA synthesis by DNA polymerase gamma. Nucleic Acids Res. 1981; 9(7):1599-613. PMC: 326785. DOI: 10.1093/nar/9.7.1599. View

Johnson A, Johnson K . Exonuclease proofreading by human mitochondrial DNA polymerase. J Biol Chem. 2001; 276(41):38097-107. DOI: 10.1074/jbc.M106046200. View

Goody R, Muller B, Restle T . Factors contributing to the inhibition of HIV reverse transcriptase by chain-terminating nucleotides in vitro and in vivo. FEBS Lett. 1991; 291(1):1-5. DOI: 10.1016/0014-5793(91)81089-q. View

Feng J, Johnson A, Johnson K, Anderson K . Insights into the molecular mechanism of mitochondrial toxicity by AIDS drugs. J Biol Chem. 2001; 276(26):23832-7. DOI: 10.1074/jbc.M101156200. View

McKenzie R, Fried M, Sallie R, Conjeevaram H, Di Bisceglie A, Park Y . Hepatic failure and lactic acidosis due to fialuridine (FIAU), an investigational nucleoside analogue for chronic hepatitis B. N Engl J Med. 1995; 333(17):1099-105. DOI: 10.1056/NEJM199510263331702. View

10.

Clayton D . Replication of animal mitochondrial DNA. Cell. 1982; 28(4):693-705. DOI: 10.1016/0092-8674(82)90049-6. View

11.

Klecker R, KATKI A, Collins J . Toxicity, metabolism, DNA incorporation with lack of repair, and lactate production for 1-(2'-fluoro-2'-deoxy-beta-D-arabinofuranosyl)-5-iodouracil in U-937 and MOLT-4 cells. Mol Pharmacol. 1994; 46(6):1204-9. View

12.

Lim S, Copeland W . Differential incorporation and removal of antiviral deoxynucleotides by human DNA polymerase gamma. J Biol Chem. 2001; 276(26):23616-23. DOI: 10.1074/jbc.M101114200. View

13.

Herskowitz A, Willoughby S, Baughman K, Schulman S, Bartlett J . Cardiomyopathy associated with antiretroviral therapy in patients with HIV infection: a report of six cases. Ann Intern Med. 1992; 116(4):311-3. DOI: 10.7326/0003-4819-116-4-311. View

14.

Lim S, Ponamarev M, Longley M, Copeland W . Structural determinants in human DNA polymerase gamma account for mitochondrial toxicity from nucleoside analogs. J Mol Biol. 2003; 329(1):45-57. DOI: 10.1016/s0022-2836(03)00405-4. View

15.

Fowler J, Brown J, Johnson K, Suo Z . Kinetic investigation of the inhibitory effect of gemcitabine on DNA polymerization catalyzed by human mitochondrial DNA polymerase. J Biol Chem. 2008; 283(22):15339-48. PMC: 2397453. DOI: 10.1074/jbc.M800310200. View

16.

Richman D, Fischl M, GRIECO M, Gottlieb M, Volberding P, Laskin O . The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. N Engl J Med. 1987; 317(4):192-7. DOI: 10.1056/NEJM198707233170402. View

17.

Johnson A, Ray A, Hanes J, Suo Z, Colacino J, Anderson K . Toxicity of antiviral nucleoside analogs and the human mitochondrial DNA polymerase. J Biol Chem. 2001; 276(44):40847-57. DOI: 10.1074/jbc.M106743200. View

18.

Carrodeguas J, Pinz K, Bogenhagen D . DNA binding properties of human pol gammaB. J Biol Chem. 2002; 277(51):50008-14. DOI: 10.1074/jbc.M207030200. View

19.

Carrodeguas J, Kobayashi R, Lim S, Copeland W, Bogenhagen D . The accessory subunit of Xenopus laevis mitochondrial DNA polymerase gamma increases processivity of the catalytic subunit of human DNA polymerase gamma and is related to class II aminoacyl-tRNA synthetases. Mol Cell Biol. 1999; 19(6):4039-46. PMC: 104363. DOI: 10.1128/MCB.19.6.4039. View

20.

Olson M, Wang Y, Elder R, Kaguni L . Subunit structure of mitochondrial DNA polymerase from Drosophila embryos. Physical and immunological studies. J Biol Chem. 1995; 270(48):28932-7. DOI: 10.1074/jbc.270.48.28932. View