scholarly journals Effect of the Y955C Mutation on Mitochondrial DNA Polymerase Nucleotide Incorporation Efficiency and Fidelity

Biochemistry ◽  
2011 ◽  
Vol 50 (29) ◽  
pp. 6376-6386 ◽  
Author(s):  
Patricia A. Estep ◽  
Kenneth A. Johnson
Keyword(s):  
Mitochondrial Dna ◽  
Dna Polymerase ◽  
Nucleotide Incorporation ◽  
Mitochondrial Dna Polymerase ◽  
Incorporation Efficiency

scholarly journals Translesion Synthesis Past Acrolein-derived DNA Adducts by Human Mitochondrial DNA Polymerase γ

2013 ◽  
Vol 288 (20) ◽  
pp. 14247-14255 ◽  
Author(s):  
Rajesh Kasiviswanathan ◽  
Irina G. Minko ◽  
R. Stephen Lloyd ◽  
William C. Copeland
Keyword(s):  
Mitochondrial Dna ◽  
Dna Synthesis ◽  
Dna Polymerase ◽  
Dna Adducts ◽  
Translesion Synthesis ◽  
Minor Groove ◽  
Purine Nucleotides ◽  
Nucleotide Incorporation ◽  
Mitochondrial Dna Polymerase ◽  
Following Error

Acrolein, a mutagenic aldehyde, is produced endogenously by lipid peroxidation and exogenously by combustion of organic materials, including tobacco products. Acrolein reacts with DNA bases forming exocyclic DNA adducts, such as γ-hydroxy-1,N2-propano-2′-deoxyguanosine (γ-HOPdG) and γ-hydroxy-1,N6-propano-2′-deoxyadenosine (γ-HOPdA). The bulky γ-HOPdG adduct blocks DNA synthesis by replicative polymerases but can be bypassed by translesion synthesis polymerases in the nucleus. Although acrolein-induced adducts are likely to be formed and persist in mitochondrial DNA, animal cell mitochondria lack specialized translesion DNA synthesis polymerases to tolerate these lesions. Thus, it is important to understand how pol γ, the sole mitochondrial DNA polymerase in human cells, acts on acrolein-adducted DNA. To address this question, we investigated the ability of pol γ to bypass the minor groove γ-HOPdG and major groove γ-HOPdA adducts using single nucleotide incorporation and primer extension analyses. The efficiency of pol γ-catalyzed bypass of γ-HOPdG was low, and surprisingly, pol γ preferred to incorporate purine nucleotides opposite the adduct. Pol γ also exhibited ∼2-fold lower rates of excision of the misincorporated purine nucleotides opposite γ-HOPdG compared with the corresponding nucleotides opposite dG. Extension of primers from the termini opposite γ-HOPdG was accomplished only following error-prone purine nucleotide incorporation. However, pol γ preferentially incorporated dT opposite the γ-HOPdA adduct and efficiently extended primers from the correctly paired terminus, indicating that γ-HOPdA is probably nonmutagenic. In summary, our data suggest that acrolein-induced exocyclic DNA lesions can be bypassed by mitochondrial DNA polymerase but, in the case of the minor groove γ-HOPdG adduct, at the cost of unprecedented high mutation rates.

scholarly journals The tamas Gene, Identified as a Mutation That Disrupts Larval Behavior in Drosophila melanogaster, Codes for the Mitochondrial DNA Polymerase Catalytic Subunit (DNApol-γ125)

Genetics ◽  
1999 ◽  
Vol 153 (4) ◽  
pp. 1809-1824 ◽  
Author(s):  
Balaji Iyengar ◽  
John Roote ◽  
Ana Regina Campos
Keyword(s):  
Mitochondrial Dna ◽  
Drosophila Melanogaster ◽  
Mutant Strain ◽  
Dna Polymerase ◽  
Complementation Group ◽  
Behavioral Changes ◽  
Catalytic Subunit ◽  
Primary Deficit ◽  
Mitochondrial Dna Polymerase ◽  
Food Substrate

AbstractFrom a screen of pupal lethal lines of Drosophila melanogaster we identified a mutant strain that displayed a reproducible reduction in the larval response to light. Moreover, this mutant strain showed defects in the development of the adult visual system and failure to undergo behavioral changes characteristic of the wandering stage. The foraging third instar larvae remained in the food substrate for a prolonged period and died at or just before pupariation. Using a new assay for individual larval photobehavior we determined that the lack of response to light in these mutants was due to a primary deficit in locomotion. The mutation responsible for these phenotypes was mapped to the lethal complementation group l(2)34Dc, which we renamed tamas (translated from Sanskrit as “dark inertia”). Sequencing of mutant alleles demonstrated that tamas codes for the mitochondrial DNA polymerase catalytic subunit (DNApol-γ125).

Human Mitochondrial DNA Polymerase Holoenzyme: Reconstitution and Characterization†

Biochemistry ◽  
2000 ◽  
Vol 39 (7) ◽  
pp. 1702-1708 ◽  
Author(s):  
Allison A. Johnson ◽  
Yu-chih Tsai ◽  
Steven W. Graves ◽  
Kenneth A. Johnson
Keyword(s):  
Mitochondrial Dna ◽  
Dna Polymerase ◽  
Human Mitochondrial Dna ◽  
Mitochondrial Dna Polymerase

The expanding clinical and pathologic spectrum of mitochondrial DNA polymerase gamma mutations

2007 ◽  
Vol 66 (5) ◽  
pp. 437
Author(s):  
Michael A. Farrell ◽  
Rachel Howley ◽  
Yazan Alderazi ◽  
Francesca Brett ◽  
Joan Moroney ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Dna Polymerase ◽  
Polymerase Gamma ◽  
Dna Polymerase Gamma ◽  
Mitochondrial Dna Polymerase
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