DNA Polymerase γ, The Mitochondrial Replicase

Kaguni, Laurie S.

doi:10.1146/annurev.biochem.72.121801.161455

Cited by 377 publications

(322 citation statements)

References 156 publications

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“…The existence of repair of oxidative damage to mtDNA was established several years ago [151][152][153]. It was also reported that mitochondrial DNA polymerase gamma (Polg) and mtDNA ligase (Lig IIIb), which are involved in mtDNA replication are also functional in mitochondrial BER [154,155]. Lig IIIb is a splice variant of the nuclear Lig IIIa, whereas Polg is unique for the mitochondria [156].…”

Section: Ber In Mitochondriamentioning

confidence: 99%

Early steps in the DNA base excision/single-strand interruption repair pathway in mammalian cells

2008

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Base excision repair (BER) is an evolutionarily conserved process for maintaining genomic integrity by eliminating several dozen damaged (oxidized or alkylated) or inappropriate bases that are generated endogenously or induced by genotoxicants, predominantly, reactive oxygen species (ROS). BER involves 4-5 steps starting with base excision by a DNA glycosylase, followed by a common pathway usually involving an AP-endonuclease (APE) to generate 3′ OH terminus at the damage site, followed by repair synthesis with a DNA polymerase and nick sealing by a DNA ligase. This pathway is also responsible for repairing DNA single-strand breaks with blocked termini directly generated by ROS. Nearly all glycosylases, far fewer than their substrate lesions particularly for oxidized bases, have broad and overlapping substrate range, and could serve as back-up enzymes in vivo. In contrast, mammalian cells encode only one APE, APE1, unlike two APEs in lower organisms. In spite of overall similarity, BER with distinct subpathways in the mammals is more complex than in E. coli. The glycosylases form complexes with downstream proteins to carry out efficient repair via distinct subpathways one of which, responsible for repair of strand breaks with 3′ phosphate termini generated by the NEIL family glycosylases or by ROS, requires the phosphatase activity of polynucleotide kinase instead of APE1. Different complexes may utilize distinct DNA polymerases and ligases. Mammalian glycosylases have nonconserved extensions at one of the termini, dispensable for enzymatic activity but needed for interaction with other BER and non-BER proteins for complex formation and organelle targeting. The mammalian enzymes are sometimes covalently modified which may affect activity and complex formation. The focus of this review is on the early steps in mammalian BER for oxidized damage.

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Section: Ber In Mitochondriamentioning

confidence: 99%

Early steps in the DNA base excision/single-strand interruption repair pathway in mammalian cells

2008

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“…The nuclear gene POLG encodes mitochondrial DNA polymerase gamma 1, which is the only polymerase known to be involved in mtDNA replication and repair in eukaryotes [55]. POLG abnormalities result in mtDNA mutations and/or multiple deletions, and are responsible for the most common cause of inherited mitochondrial diseases in children and adults [56].…”

Section: Polg-related Disordersmentioning

confidence: 99%

Mitochondrial Disease in Childhood: Nuclear Encoded

2013

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Primary mitochondrial disorders are clinically and genetically heterogeneous, caused by an alteration(s) in either mitochondrial DNA or nuclear DNA, and affect the respiratory chain's ability to undergo oxidative phosphorylation, leading to decreased production of adenosine triphosphophate and subsequent energy failure. These disorders may present at any age, but children tend to have an acute onset of disease compared with subacute or slowly progressive presentation in adults. Varying organ involvement also contributes to the phenotypic spectrum seen in these disorders. The childhood presentation of primary mitochondrial disease is mainly due to nuclear DNA mutations, with mitochondrial DNA mutations being less frequent in childhood and more prominent in adulthood disease. The clinician should be aware of the pediatric presentation of mitochondrial disease and have an understanding of the myriad of nuclear genes responsible for these disorders. The nuclear genes can be best understood by utilizing a classification system of location and function within the mitochondria.

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“…7,8 Mitochondrial DNA, a 16.5-kb circular double-stranded molecule, is replicated by an assembly of enzymes and proteins consisting of DNA polymerase g (pol g), ssDNAbinding protein, DNA helicase and various accessory proteins and transcription factors. 9 Mitochondrial DNA is prone to mutations, as it is localized near the inner mitochondrial membrane in which reactive oxygen species are generated. In addition, mtDNA lacks histone protection and highly efficient DNA repair mechanisms.…”

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confidence: 99%

p53 in mitochondria enhances the accuracy of DNA synthesis

et al. 2008

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Mitochondrial localization of p53 was observed in stressed and unstressed cells. p53 is involved in DNA repair and apoptosis. It exerts physical and functional interactions with mitochondrial DNA and DNA polymerase c (pol c). The functional cooperation of p53 and pol c during DNA synthesis was examined in the mitochondrial fraction of p53-null H1299 cells, as the source of pol c. The results show that p53 may affect the accuracy of DNA synthesis in mitochondria: (1) the excision of a misincorporated nucleotide increases in the presence of (a) recombinant wild-type p53 (wtp53); (b) cytoplasmic fraction of LCC2 cells expressing endogenous wtp53 (but not specifically pre-depleted fraction); (c) cytoplasmic extract of H1299 cells overexpressing wtp53, but not exonuclease-deficient mutant p53-R175H. (2) Mitochondrial extracts of HCT116(p53 þ / þ ) cells display higher exonuclease activity compared with that of HCT116(p53À/À) cells. Addition of exogenous p53 complements the HCT116(p53À/À) mitochondrial extract mispair excision. Furthermore, the misincorporation was lower in the mitochondrial fraction of HCT116(p53 þ / þ ) cells as compared with that of HCT116(p53À/À) cells. The tumor suppressor protein p53 represents a central factor for the maintenance of genome stability and for the suppression of cancer. 1 p53 is present at low levels in unstressed cells, but after exposure to various stress signals, the protein is stabilized and activated by a series of post-translational modifications. p53 is involved in the induction of cell-cycle arrest and apoptosis through transcriptional activation of target genes. 2 p53 displays multicompartmental functions in the cell. Interestingly, in response to multiple death stimuli, mitochondrial p53 targeting occurs in a wide spectrum of cell types, where it elicits a series of responses that can promote an apoptosis through a transcription-independent mechanism. 3,4 Several lines of evidence support a connection between p53 and mitochondrion. Mitochondrial p53 levels are proportional to total p53 levels, and a small fraction of protein is associated with mitochondrial DNA (mtDNA) in the absence of exogenous stress, thus implying a non-apoptotic function for mitochondrial p53. 5 Furthermore, translocation of p53 to mitochondria was observed in various cells (e.g., MCF-7 and HCT116) independent of apoptosis. 6 p53 may be a component of a stress response pathway that involves the upregulation of mitochondrial repair in mouse liver and cancer cells, suggesting the potential role of p53 in maintaining mtDNA stability. 7,8 Mitochondrial DNA, a 16.5-kb circular double-stranded molecule, is replicated by an assembly of enzymes and proteins consisting of DNA polymerase g (pol g), ssDNAbinding protein, DNA helicase and various accessory proteins and transcription factors. 9 Mitochondrial DNA is prone to mutations, as it is localized near the inner mitochondrial membrane in which reactive oxygen species are generated. In addition, mtDNA lacks histone protection and highly efficient DNA repair...

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DNA Polymerase γ, The Mitochondrial Replicase

Cited by 377 publications

References 156 publications

Early steps in the DNA base excision/single-strand interruption repair pathway in mammalian cells

Early steps in the DNA base excision/single-strand interruption repair pathway in mammalian cells

Mitochondrial Disease in Childhood: Nuclear Encoded

p53 in mitochondria enhances the accuracy of DNA synthesis

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