REXO2 Is an Oligoribonuclease Active in Human Mitochondria

Bruni, Francesco; Gramegna, Pasqua; Oliveira, Jorge M. A.; Lightowlers, Robert N.

doi:10.1371/journal.pone.0064670

Cited by 53 publications

(58 citation statements)

References 51 publications

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“…Cluster 2 was associated with anatomical morphogenesis and cell adhesion, and cluster 3 with genes involved in leukocyte activation (Fig 8c, Supplementary Table 2). DNA methylation and gene expression changes characteristic for clusters 1 and 4 were found at regions near Prdm1 and Il10 , important regulators of plasma cell biology 20,29 , as well as C1qbp and Rexo2 , genes important for mitochondrial metabolism 39,40 (Fig. 8d).…”

Section: Resultsmentioning

confidence: 99%

Plasma cell differentiation is coupled to division-dependent DNA hypomethylation and gene regulation

et al. 2016

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The epigenetic processes that regulate antibody secreting plasma cells are not well understood. Here, analysis of plasma cell differentiation revealed DNA hypomethylation of 10% of CpG loci that were overrepresented at enhancers. Inhibition of DNA methylation enhanced plasma cell commitment in a cell division-dependent manner. Examination of in vivo differentiating B cells stratified by cell division revealed a 5-fold increase in mRNA transcription coupled to DNA hypomethylation. Demethylation occurred first at binding motifs of NF-κB and AP-1 and later at those for IRF and Oct-2, and were coincident with activation and differentiation gene expression programs. These data provide mechanistic insight into the cell-division coupled transcriptional and epigenetic reprogramming and suggest DNA hypomethylation reflects the cis-regulatory history of plasma cell differentiation.

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Section: Resultsmentioning

confidence: 99%

Plasma cell differentiation is coupled to division-dependent DNA hypomethylation and gene regulation

et al. 2016

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“…Both are nuclear genes that influence mtDNA metabolism, MPV17 contributes to mtDNA maintenance (3), whereas MPV17L2 has a role in mitochondrial protein synthesis (this report). Notwithstanding these differences, the immunocytochemistry data indicate that there is a major disturbance of mtDNA organization when MPV17L2 is scarce (Figures 3B and 8), which in view of MPV17L2's ribosomal association suggests perturbed ribosome-nucleoid interactions (13,34,35). …”

Section: Discussionmentioning

confidence: 96%

MPV17L2 is required for ribosome assembly in mitochondria

Rosa¹,

Durigon²,

Pearce

et al. 2014

Nucleic Acids Res

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MPV17 is a mitochondrial protein of unknown function, and mutations in MPV17 are associated with mitochondrial deoxyribonucleic acid (DNA) maintenance disorders. Here we investigated its most similar relative, MPV17L2, which is also annotated as a mitochondrial protein. Mitochondrial fractionation analyses demonstrate MPV17L2 is an integral inner membrane protein, like MPV17. However, unlike MPV17, MPV17L2 is dependent on mitochondrial DNA, as it is absent from ρ0 cells, and co-sediments on sucrose gradients with the large subunit of the mitochondrial ribosome and the monosome. Gene silencing of MPV17L2 results in marked decreases in the monosome and both subunits of the mitochondrial ribosome, leading to impaired protein synthesis in the mitochondria. Depletion of MPV17L2 also induces mitochondrial DNA aggregation. The DNA and ribosome phenotypes are linked, as in the absence of MPV17L2 proteins of the small subunit of the mitochondrial ribosome are trapped in the enlarged nucleoids, in contrast to a component of the large subunit. These findings suggest MPV17L2 contributes to the biogenesis of the mitochondrial ribosome, uniting the two subunits to create the translationally competent monosome, and provide evidence that assembly of the small subunit of the mitochondrial ribosome occurs at the nucleoid.

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“…Subcellular fractions were prepared as described previously (Bruni et al, 2013) with few modifications. HEK293 cells were harvested, resuspended in HB (0.6 M Mannitol, 10 mM Tris-HCl pH 7.4, 1 mM EGTA), subjected to standard differential centrifugation and the post-mitochondrial supernatant (cytosolic fraction) was retained.…”

Section: Methodsmentioning

confidence: 99%

The GABA Transaminase, ABAT, Is Essential for Mitochondrial Nucleoside Metabolism

et al. 2015

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Summary ABAT is a key enzyme responsible for catabolism of principal inhibitory neurotransmitter gamma-aminobutyric acid (GABA). We report an essential role for ABAT in a seemingly unrelated pathway, mitochondrial nucleoside salvage, and demonstrate that mutations in this enzyme cause an autosomal recessive neurometabolic disorder and mtDNA depletion syndrome (MDS). We describe a family with encephalomyopathic MDS caused by a homozygous missense mutation in ABAT that results in elevated GABA in subjects’ brains as well as decreased mtDNA levels in subjects’ fibroblasts. Nucleoside rescue and co-IP experiments pinpoint that ABAT functions in the mitochondrial nucleoside salvage pathway to facilitate conversion of dNDPs to dNTPs. Pharmacological inhibition of ABAT through the irreversible inhibitor Vigabatrin caused depletion of mtDNA in photoreceptor cells that was prevented through addition of dNTPs in cell culture media. This work reveals ABAT as a connection between GABA metabolism and nucleoside metabolism and defines a neurometabolic disorder that includes MDS.

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REXO2 Is an Oligoribonuclease Active in Human Mitochondria

Cited by 53 publications

References 51 publications

Plasma cell differentiation is coupled to division-dependent DNA hypomethylation and gene regulation

Plasma cell differentiation is coupled to division-dependent DNA hypomethylation and gene regulation

MPV17L2 is required for ribosome assembly in mitochondria

The GABA Transaminase, ABAT, Is Essential for Mitochondrial Nucleoside Metabolism

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