Disease relevance of Polg

• We have previously shown that mice with an error-prone version of PolgA accumulate higher levels of somatic mtDNA mutations resulting in a premature aging phenotype [1].
• Recently, several antiviral nucleoside analogs were reported to inhibit DNA polymerase gamma after intracellular phosphorylation and cause severe chronic toxicity [2].

High impact information on Polg

• A human Pol gamma B mutant lacking the four-helix bundle failed to dimerize in solution or to stimulate the catalytic subunit Pol gamma A, but retained the ability to bind with Pol gamma A to a primer-template construct, indicating that the functional holoenzyme contains two Pol gamma B molecules [3].
• These results suggest that the Pol gamma B dimer contains distinct sites for Pol gamma A binding, dimerization, and DNA binding [3].
• CONCLUSIONS: After repeated doses of ethanol, the accumulation of unrepaired mtDNA lesions (possibly involving lipid peroxidation-induced adducts) blocks the progress of polymerase gamma on mtDNA and prevents adaptive mtDNA resynthesis, causing prolonged hepatic mtDNA depletion [4].
• Mitochondrial DNA polymerase gamma is essential for mammalian embryogenesis [1].
• In vitro, tacrine impaired DNA polymerase gamma-mediated DNA replication and also poisoned topoisomerases I and II to increase the relaxation of a supercoiled plasmid [5].

Biological context of Polg

• Mitochondrial DNA (mtDNA) polymerase gamma (Polg) is a heterodimeric enzyme containing a Pol I-like catalytic core (PolgA) and an accessory subunit [1].
• DNA polymerase gamma is encoded in the nucleus but localizes in the mitochondria, and is responsible for the mitochondrial DNA replication [2].
• The second insertion site is the 3' noncoding region of the DNA polymerase gamma (PolG) gene on chromosome 7 [6].
• The 3'-5' exonuclease proofreading activity of Pol gamma ensures accuracy of mtDNA replication in both yeast and humans, while the role of base excision repair in mtDNA error avoidance remains debated [7].
• The N-terminal part of the sequence contains a 13 glutamine stretch encoded by a CAG trinucleotide repeat which is not found in the other DNA polymerases gamma (Pol gamma) [8].

Anatomical context of Polg

• In mitochondria, DNA polymerase-gamma (Polgamma) is believed to be the sole polymerase and is therefore assumed to function in mitochondrial BER [9].
• Peak activity of mitochondrial DNA polymerase-gamma occurred concurrent to the interval of accelerated organelle DNA synthesis [10].
• Analysis by 125I-labeled peptide mapping indicates that the Mr 47 000 polypeptide in the mouse myeloma DNA polymerase gamma preparation is structurally related to the Mr 47 000 polypeptide of chick embryo DNA polymerase gamma (Yamaguchi, M., Matsukage, A. and Takahashi, T. (1980) J. Biol. Chem. 255, 7002-7009) [11].
• Poly(2'-fluoro-2'-deoxyadenylic acid) (poly(dAfl)) and poly(2'-deoxycytidylic acid) (poly(dCfl)) were tested as templates in DNA synthesis reactions catalyzed by Xenopus laevis oocytes DNA polymerase alpha, mouse cell DNA polymerase gamma and avian myeloblastis virus (AMV) reverse transcriptase [12].

Associations of Polg with chemical compounds

• It is also demonstrated that the response of DNA polymerase gamma to N-ethylmaleimide is template dependent, and that DNA polymerase alpha has an authentic (albeit small) activity with poly(rA).oligo(dT) [13].
• The 21-tungsto-9-antimoniate ammonium salt (HPA23), known as an antiviral agent, has been shown to be a potent inhibitor of both human and murine DNA polymerase alpha and murine DNA polymerase gamma [14].
• Sodium dodecyl sulfate polyacrylamide gel electrophoresis of protein fractions obtained by DNA-cellulose column chromatography revealed that the amount of a polypeptide of Mr = 47 000 changed proportionally with DNA polymerase gamma activity [11].
• Mouse myeloma DNA polymerase gamma was extensively purified to a final specific activity of 156 000 units (nmol dTMP incorporation per h) per mg protein on (rA)n.(dT)12-18 as a template primer [11].

Other interactions of Polg

• Cl-F-ara-ATP was not a potent inhibitor of DNA polymerase beta, DNA polymerase gamma, or DNA primase.(ABSTRACT TRUNCATED AT 400 WORDS)[15]
• Polymerase gamma gap-filing activity was less efficient in p53 knockout extracts, but it was complemented with the addition of recombinant p53 [16].

Analytical, diagnostic and therapeutic context of Polg

• Two and 24 hours after the fourth dose, long polymerase chain reaction experiments showed DNA lesions that blocked the progress of the polymerases and in organello mtDNA synthesis was decreased, although DNA polymerase gamma activity was unchanged with synthetic templates [4].
• Changes of mitochondrial DNA polymerase-gamma activity in synchronized mouse cell cultures [10].

References