The efficiency of the translesion synthesis across abasic sites by mitochondrial DNA polymerase is low in mitochondria of 3T3 cells

Kozhukhar, Natalya; Spadafora, Domenico; Fayzulin, Rafik; Shokolenko, Inna; Alexeyev, Mikhail

doi:10.3109/19401736.2015.1089539

Cited by 14 publications

(19 citation statements)

References 40 publications

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“…The authors also speculated that TFAM might not inhibit DNA repair in vivo (66). Our observation that TFAM promotes strand cleavage at AP sites suggests an active role of TFAM in processing ubiquitous AP sites, which may account for the rapid DNA depletion resulting from mitochondrial AP sites (36). Such strand cleavage activity may also act redundantly with APE1 or bifunctional glycosylases in their strand-scission activities.…”

Section: Discussionmentioning

confidence: 83%

“…TFAM Promotes Strand Cleavage at AP Sites. Previous work has shown that mtDNA elimination counteracts the mutagenicity of AP sites in human and mouse cells, as evidenced by a decline in mtDNA copy number and a moderate mutation load after the induction of mitochondrial AP sites (36). Nonetheless, the chemical and molecular basis of AP-DNA elimination remains an important unsolved question.…”

Section: Discussionmentioning

confidence: 99%

“…MtDNA degradation is activated in response to difficult-to-repair DNA lesions or excessive DNA damage, and is thought to be nonspecific to DNA lesion types (27)(28)(29)(30)(31)(32). Remarkably, Alexeyev and colleagues demonstrated that mitochondrial AP sites trigger mtDNA degradation in human and mouse cells (29,36). The observed DNA loss is rapid and not likely due to autophagy, mitophagy, or apoptosis (30,32).…”

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confidence: 99%

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Mitochondrial transcription factor A promotes DNA strand cleavage at abasic sites

Boyd

Tree

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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In higher eukaryotic cells, mitochondria are essential subcellular organelles for energy production, cell signaling, and the biosynthesis of biomolecules. The mitochondrial DNA (mtDNA) genome is indispensable for mitochondrial function because it encodes protein subunits of the electron transport chain and a full set of transfer and ribosomal RNAs. MtDNA degradation has emerged as an essential quality control measure to maintain mtDNA and to cope with mtDNA damage resulting from endogenous and environmental factors. Among all types of DNA damage known, abasic (AP) sites, sourced from base excision repair and spontaneous base loss, are the most abundant endogenous DNA lesions in cells. In mitochondria, AP sites trigger rapid DNA loss; however, the mechanism and molecular factors involved in the process remain elusive. Herein, we demonstrate that the stability of AP sites is reduced dramatically upon binding to a major mtDNA packaging protein, mitochondrial transcription factor A (TFAM). The half-life of AP lesions within TFAM–DNA complexes is 2 to 3 orders of magnitude shorter than that in free DNA, depending on their position. The TFAM-catalyzed AP-DNA destabilization occurs with nonspecific DNA or mitochondrial light-strand promoter sequence, yielding DNA single-strand breaks and DNA–TFAM cross-links. TFAM–DNA cross-link intermediates prior to the strand scission were also observed upon treating AP-DNA with mitochondrial extracts of human cells. In situ trapping of the reaction intermediates (DNA–TFAM cross-links) revealed that the reaction proceeds via Schiff base chemistry facilitated by lysine residues. Collectively, our data suggest a novel role of TFAM in facilitating the turnover of abasic DNA.

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Mitochondrial transcription factor A promotes DNA strand cleavage at abasic sites

Boyd

Tree

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…According to "C-rule" the loss of adenines in mtDNA would give rise A→G transitions, while the loss of guanines would be non-mutagenic (Zhang et al 2006). However, recent study demonstrated that enzymatically created AP sites in mtDNA of mouse cells are weakly mutagenic, and that repair and DNA degradation occur more often than TLS of AP sites (Kozhukhar et al 2016). More studies are required to identify a possible origin of A H →G H transitions in mtDNA.…”

Section: A Hypothesis On the Origin Of Mtdna Mutationsmentioning

confidence: 99%

DNA repair and mutagenesis in vertebrate mitochondria: evidence for the asymmetric DNA strand inheritance

Matkarimov

Saparbaev

2019

Preprint

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A variety of endogenous and exogenous factors induce chemical and structural alterations to cellular DNA, as well as errors occurring throughout DNA synthesis. These DNA damages are cytotoxic, miscoding, or both, and are believed to be at the origin of cancer and other age related diseases. A human cell, in addition to nuclear DNA, contains thousands copies of mitochondrial DNA (mtDNA), a double-stranded, circular molecule of 16,569 bp. It was proposed that mtDNA is a critical target for reactive oxygen species (ROS), by-products of the oxidative phosphorylation (OXPHOS), generated in the organelle during aerobic respiration. Indeed, oxidative damage to mtDNA are more extensive and persistent as compared to that of nuclear DNA. Although, transversions are the hallmarks of mutations induced by ROS, paradoxically, the majority of mtDNA mutations that occurred during ageing and cancer are transitions. Furthermore, these mutations exhibit a striking strand orientation bias: T→C/G→A transitions preferentially occur on the Light strand, whereas C→T/A→G on the Heavy strand of mtDNA. Here, we propose that the majority of mtDNA progenies, created after multiple rounds of DNA replication, are derived from the Heavy strand only, due to asymmetric replication of the DNA strand anchored to inner membrane via D-loop structure.

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“…These isoforms derive from transcription from two distinct start sites as well as from alternative splicing of the mRNAs transcribed from the ung gene [5]. The role of UNG1 in the processing of uracil at mitochondria is not well defined and needs additional studies [6,7]. UNG2 is the nuclear DNA glycosylase [8] and its turnover is regulated by cell-cycle specific phosphorylations by cyclin-dependent kinases [9,10] and by a TP53-dependent phosphatase [9,10].…”

Section: The Family Of the Udgsmentioning

confidence: 99%

Single nucleotide polymorphisms in DNA glycosylases: From function to disease

D’Errico¹,

Parlanti²,

Pascucci³

et al. 2017

Free Radical Biology and Medicine

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Oxidative stress is associated with a growing number of diseases that span from cancer to neurodegeneration. Most oxidatively induced DNA base lesions are repaired by the base excision repair (BER) pathway which involves the action of various DNA glycosylases. There are numerous genome wide studies attempting to associate single-nucleotide polymorphisms (SNPs) with predispositions to various types of disease; often, these common variants do not have significant alterations in their biochemical function and do not exhibit a convincing phenotype. Nevertheless several lines of evidence indicate that SNPs in DNA repair genes may modulate DNA repair capacity and contribute to risk of disease. This overview provides a convincing picture that SNPs of DNA glycosylases that remove oxidatively generated DNA lesions are susceptibility factors for a wide disease spectrum that includes besides cancer (particularly lung, breast and gastrointestinal tract), cochlear/ocular disorders, myocardial infarction and neurodegenerative disorders which can be all grouped under the umbrella of oxidative stress-related pathologies.

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The efficiency of the translesion synthesis across abasic sites by mitochondrial DNA polymerase is low in mitochondria of 3T3 cells

Cited by 14 publications

References 40 publications

Mitochondrial transcription factor A promotes DNA strand cleavage at abasic sites

Mitochondrial transcription factor A promotes DNA strand cleavage at abasic sites

DNA repair and mutagenesis in vertebrate mitochondria: evidence for the asymmetric DNA strand inheritance

Single nucleotide polymorphisms in DNA glycosylases: From function to disease

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