Mitochondrial DNA repair and replication proteins revealed by targeted chemical probes

Wisnovsky, Simon; Jean, Sae Rin

doi:10.1038/nchembio.2102

Cited by 81 publications

(121 citation statements)

References 41 publications

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“…5B). The Pearson’s Coefficient value for pol β was similar to other mitochondrial proteins previously reported [53]. Taken together, these morphological results further corroborate the biochemical data in Figs.…”

Section: Resultssupporting

confidence: 91%

“…Although mitochondria import many different proteins from the cytosol, more than 50% of these proteins do not have a classical mitochondrial-targeting sequence, but instead have alternate mechanisms of mitochondrial targeting [71]. Thus, the mechanism of pol β mitochondrial transport is unknown, but this also is true for a number of other mitochondrial DNA enzymes, including Tdp1, MSH5, XPD, MSH5, PARP-1 and pol θ [31,33,53,70,72,73]. …”

Section: Discussionmentioning

confidence: 99%

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DNA polymerase β: A missing link of the base excision repair machinery in mammalian mitochondria

et al. 2017

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Mitochondrial genome integrity is fundamental to mammalian cell viability. Since mitochondrial DNA is constantly under attack from oxygen radicals released during ATP production, DNA repair is vital in removing oxidatively generated lesions in mitochondrial DNA, but the presence of a strong base excision repair system has not been demonstrated. Here, we addressed the presence of such a system in mammalian mitochondria involving the primary base lesion repair enzyme DNA polymerase (pol) β. Pol β was localized to mammalian mitochondria by electron microscopic-immunogold staining, immunofluorescence co-localization and biochemical experiments. Extracts from purified mitochondria exhibited base excision repair activity that was dependent on pol β. Mitochondria from pol β-deficient mouse fibroblasts had compromised DNA repair and showed elevated levels of superoxide radicals after hydrogen peroxide treatment. Mitochondria in pol β-deficient fibroblasts displayed altered morphology by electron microscopy. These results indicate that mammalian mitochondria contain an efficient base lesion repair system mediated in part by pol β and thus pol β plays a role in preserving mitochondrial genome stability.

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Section: Resultssupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

DNA polymerase β: A missing link of the base excision repair machinery in mammalian mitochondria

et al. 2017

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“…Because XPA status has been reported to affect mitochondrial function and mitophagy [20,31], we examined gene expression in relevant pathways. To narrow down the analysis, we focused on genes with a fold change (FC) of 1.5 (Table 1) or 2 (Table 2) in each pair of cell lines.…”

Section: Resultsmentioning

confidence: 99%

“…This genomic stress is clearly associated with mitochondrial dysfunction, and it is possible that exposed DNA ends induce a signal for disruption of key mitochondrial gene expression [41–44]. Another example is provided by an siRNA screen for factors that reduce sensitivity to a mitochondria-targeted DNA damaging agent [31]. Many DNA repair factors, including XPA, were detected in this screen.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional consequences of XPA disruption in human cell lines

et al. 2017

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Nucleotide excision repair (NER) in mammalian cells requires the xeroderma pigmentosum group A protein (XPA) as a core factor. Remarkably, XPA and other NER proteins have been detected by chromatin immunoprecipitation at some active promoters, and NER deficiency is reported to influence the activated transcription of selected genes. However, the global influence of XPA on transcription in human cells has not been determined. We analyzed the human transcriptome by RNA sequencing (RNA-Seq). We first confirmed that XPA is confined to the cell nucleus even in the absence of external DNA damage, in contrast to previous reports that XPA is normally resident in the cytoplasm and is imported following DNA damage. We then analyzed four genetically matched human cell line pairs deficient or proficient in XPA. Of the ∼14,000 genes transcribed in each cell line, 325 genes (2%) had a significant XPA-dependent directional change in gene expression that was common to all four pairs (with a false discovery rate of 0.05). These genes were enriched in pathways for the maintenance of mitochondria. Only 27 common genes were different by more than 1.5-fold. The most significant hits were AKR1C1 and AKR1C2, involved in steroid hormone metabolism. AKR1C2 protein was lower in all of the immortalized XPA-deficient cells. Retinoic acid treatment led to modest XPA-dependent activation of some genes with transcription-related functions. We conclude that XPA status does not globally influence human gene transcription. However, XPA significantly influences expression of a small subset of genes important for mitochondrial functions and steroid hormone metabolism. The results may help explain defects in neurological function and sterility in individuals with xeroderma pigmentosum.

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“…Subsequent work showed that TNF-α-mediated mtDNA damage requires TNF receptors and ROS production; moreover, this mtDNA damage involves binding of p53 to TFAM (97). Screening for novel mtDNA repair factors has identified the novel mitochondrial DNA polymerase theta (POLθ) that is recruited to the mitochondria when under oxidative stress (98). Moreover, damaged mtDNA appears to be released from the organelle, where it acts as a pro-inflammatory signal in a variety of contexts (99).…”

Section: Mitochondrial and Mtdna Damagementioning

confidence: 99%

The little big genome the organization of mitochondrial DNA

Garcia¹,

Jones²,

Ramos

et al. 2017

Front Biosci

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The small (16,569 base pair) human mitochondrial genome plays a significant role in cell metabolism and homeostasis. Mitochondrial DNA (mtDNA) contributes to the generation of complexes which are essential to oxidative phosphorylation (OXPHOS). As such, mtDNA is directly integrated into mitochondrial biogenesis and signaling and regulates mitochondrial metabolism in concert with nuclear-encoded mitochondrial factors. Mitochondria are a highly dynamic, pleiomorphic network that undergoes fission and fusion events. Within this network, mtDNAs are packaged into structures called nucleoids which are actively distributed in discrete foci within the network. This sensitive organelle is frequently disrupted by insults such as oxidants and inflammatory cytokines, and undergoes genomic damage with double- and single-strand breaks that impair its function. Collectively, mtDNA is emerging as a highly sensitive indicator of cellular stress, which is directly integrated into the mitochondrial network as a contributor of a wide range of critical signaling pathways.

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Mitochondrial DNA repair and replication proteins revealed by targeted chemical probes

Cited by 81 publications

References 41 publications

DNA polymerase β: A missing link of the base excision repair machinery in mammalian mitochondria

DNA polymerase β: A missing link of the base excision repair machinery in mammalian mitochondria

Transcriptional consequences of XPA disruption in human cell lines

The little big genome the organization of mitochondrial DNA

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