DNA polymerase gamma

Lewis, W., Levine, E.S., Griniuviene, B., Tankersley, K.O., Colacino, J.M., Sommadossi, J.P., Watanabe, K.A. and Perrino, F.W. (1996) Fialuridine and its metabolites inhibit DNA polymerase gamma at sites of multiple adjacent analog incorporation, decrease mtDNA abundance, and cause mitochondrial structural defects in cultured hepatoblasts. Proceedings of the National Academy of Sciences of the United States of America, 93, 3592-3597. 

Proliferation Inhibitor of DNA polymerase-gamma (e.g., nucleoside reverse transcriptase inhibitors) inhibition of mitochondrial protein synthesis (e.g., oxazolidinone antibiotics) mitochondrial DNA mutation (e.g.. oxidative injury by ethanol)... 

There are specific fiuorescent dyes for specific pathologies created by specific drug classes, such as phospholipidosis from cationic amphiphilic drugs [18, 19], mitochondrial DNA depletion by nucleoside reverse transcriptase inhibitors that also inhibit mitochondrial DNA polymerase gamma and redox cyclers that produce reactive oxygen species. The complex mechanism of statin-induced toxicity is demonstrated vith early sublethal effects on apoptosis, mitochondrial function and calcium homeostasis [20]. 

All NRTIs may be associated with mitochondrial toxicity, probably owing to inhibition of mitochondrial DNA polymerase gamma. Less commonly, lactic acidosis with hepatic steatosis may occur, which can be fatal. NRTI treatment should be suspended in the setting of rapidly rising aminotransferase levels, progressive hepatomegaly, or metabolic acidosis of unknown cause. The thymidine analogues zidovudine and stavudine may be particularly associated with dyslipidemia and insulin resistance. Also,... 

Kaguni, L.S. (2004) DNA polymerase gamma, the mitochondrial replicase. Annual Review of Biochemistry 73, 293-320. 

In vitro, NRTIs reduce mitochondrial DNA, most likely by inhibiting mitochondrial DNA polymerase gamma. Heterogeneous toxicity profiles of different NRTIs in vivo may be related to variable tissue sensitivity, cell entry, and drug phosphorylation. Therefore, each NRTI has a specific adverse effect profile (Table 2 (11)), but any feature of mitochondrial toxicity must be considered with all NRTIs. A major problem of mitochondrial toxicity is its delayed onset, sometimes after several months of treatment. 

Subsequent reports described a syndrome of type B lactic acidosis in patients treated with zidovudine and other nucleoside reverse transcriptase inhibitors, including stavudine, lamivudine, and didanosine which has also been attributed to mitochondrial DNA toxicity [95-106]. There are five types of DNA polymerase in human cells that catalyze the synthesis of new complementary DNA from the original DNA template (HIV encodes a reverse transcriptase DNA polymerase which uses RNA as the template). The active triphosphate metabolites of zidovudine, didanosine, and stavudine inhibit DNA polymerase gamma in mitochondria, block the elongation of mitochondrial DNA, and deplete mitochondrial DNA [91-93,101,105-108]. The link between NRTl effects on mitochondrial DNA and lactic acidosis is not entirely clear but is most likely related to disturbances of oxidative phosphorylation and impaired pyruvate metabolism leading to lactate accumulation. 

Copeland WC, Longley MJ (2003) DNA polymerase gamma in mitochondrial DNA replication and repair. Sci World J 3 34-44... 

B. Hepatic steatosis, severe iactic acidosis, and iipodystrophy may be due to inhibition of DNA polymerase-gamma, which depletes mitochondrial DNA, oausing mitoohondrial dysfunction. Mitochondrial RNA formation may also be inhibited. 

Carrodeguas, J. A., Theis, K., Bogenhagen, D. F., and Kisker, C. (2001). Crystal structure and deletion analysis show that the accessory subunit of mammalian DNA polymerase gamma, Pol gamma B, functions as a homodimer. Mol. Cell 7, 43-54. 

Lim, S. E., Longley, M. J., and Copeland, W. G. (1999). The mitochondrial p55 accessory subunit of human DNA polymerase gamma enhances DNA binding, promotes processive DNA synthesis, and confers N-ethyhnaleimide resistance. 

Ponamarev, M. V., Longley, M. J., Nguyen, D., Kunkel, T. A., and Gopeland, W. C. (2002). Active site mutation in DNA polymerase gamma associated vdth progressive external ophthalmoplegia causes error-prone DNA synthesis. J. Biol Chem. 277, 15225-15228. 

Lim, S. E., Copeland, W. C. (2001). Differential incorporation and removal of anitivral deoxynucleotides by human DNA polymerase gamma. J Biol Chem, 276(26), 23616-23623. 

Bailey CM, Kasiviswanathan R, Copeland WC, Anderson KS. R964C mutation of DNA polymerase gamma imparts increased stavudine toxicity by decreasing nucleoside analog discrimination and impairing polymerase activity. Antimicrob Agents Chemother 2009 53(6) 2610-2. 

Jeruzalmi D, O Donnell M, Kuriyan J. Crystal structure of the processivity clamp loader gamma (gamma) complex of E. coli DNA polymerase III. Cell 2001 106 429-441. 

Glover BP, McHenry CS. The DnaX-binding subunits delta and psi are bound to gamma and not tau in the DNA polymerase III holoenzyme. J. Biol. Chem. 2000 275 3017-3020. 

Minko, 1. G., Washington, M. T., Kanuri, M., Prakash, L., Prakash, S., and Lloyd, R. S. (2003). Translesion synthesis past acrolein-derived DNA adduct, gamma-hydroxypropanodeoxyguanosine, by yeast and human DNA polymerase r). J. Biol. Chem. 278, 784-790. 

The key step in a synthesis of cyclo-5,6-dihydro-2 -deoxyuridine, a major product of gamma irradiation of deoxygenated aqueous solutions of deoxycytidine, is the cyclization of aldehyde 33 using BuaSnH and AIBN, to give 34 of stereochemistry as indicated. The method was previously used for the thymidine analogue (J. Chem. Soc., Perkin Trans. 1,1999,1257). Both the uridine and thymidine analogues were incorporated into oligodeoxynucleotides, where they acted as blocks for DNA polymerases. ... 

Richardson, R, Kuchta, R., Mazurkiewicz, A., Richardson, K. (2000). Polymerization of 2 -fluoro- and 2 -0-methyl-dNTPs by human DNA polymerase alpha, polymerase gamma, and pri-mase. Biochem Pharmacol, 59 (9), 1045-1052. 

Enhanced rate of DNA strand break repair by hyper-expression of poly(ADP-ribose) polymerase cDNA. In the data in Fig. 1 above, we established that a significantly increased potential for poly(ADP-ribosyl)ation would exist around 2 days after transfection with pcD-12. We decided to use this time window to directly test whether poly(ADP-ribosyl)ation is involved in DNA repair by measuring the resealing of X-ray induced DNA strand breaks (8). Cos cells were prelabeled with [i C]thymidine for two days, after which cells were either mock transfected, transfected with pcC-12 or carried through without any transfection protocol. After 44 hr, the cells were irradiated with 2000 rads on ice and immediately allowed to repair at 37 C. Cells were maintained on ice until assayed by alkaline elution. Unrepaired SSB (single strand breaks) m experimental DNA were compared to the control gamma-ray induced SSB and expressed as the radiation dose that would produce Rad-equivalent breaks. The alkaline elution method used was the short assay to detect SSB up to 3000 SSB rad-equivalents. 

---