Somatic nuclear mitochondrial DNA insertions are prevalent in the human brain and accumulate over time in fibroblasts

Zhou, Weichen; Karan, Kalpita R; Gu, Wenjin; Klein, Hans‐Ulrich; Sturm, Gabriel; Bennett, David A.; Hirano, Michio; Picard, Martin; Mills, Ryan E.

doi:10.1101/2023.02.03.527065

Cited by 3 publications

(4 citation statements)

References 95 publications

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“…We therefore wondered whether cellular senescence drives de novo nuclear integration events of mtDNA in IMR-90 cells and pursued two experimental strategies, first by bioinformatic screening of WGS data and second after enrichment of nuclear DNA by an AluScan-PCR approach. Regarding the first approach, a recently published analysis on human brain and circulating immune cells together with an analysis of human fibroblasts revealed a gradual accumulation of numts with age ( Zhou et al, 2023 ), using WGS data and applying bioinformatic screens for mtDNA paralogs physically linked to GRCh37 chromosomal flanks. In our datasets obtained for the two experimental approaches comparing proliferative and senescent IMR-90, we managed to identify 79 de novo numts of which 13 were found in the first WGS data set, 55 in the second WGS data set and 11 in the AluScan Seq data.…”

Section: Discussionmentioning

confidence: 99%

Generation of somatic de novo structural variation as a hallmark of cellular senescence in human lung fibroblasts

Woronzow,

Möhner,

Remane

et al. 2023

Front. Cell Dev. Biol.

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Cellular senescence is characterized by replication arrest in response to stress stimuli. Senescent cells accumulate in aging tissues and can trigger organ-specific and possibly systemic dysfunction. Although senescent cell populations are heterogeneous, a key feature is that they exhibit epigenetic changes. Epigenetic changes such as loss of repressive constitutive heterochromatin could lead to subsequent LINE-1 derepression, a phenomenon often described in the context of senescence or somatic evolution. LINE-1 elements decode the retroposition machinery and reverse transcription generates cDNA from autonomous and non-autonomous TEs that can potentially reintegrate into genomes and cause structural variants. Another feature of cellular senescence is mitochondrial dysfunction caused by mitochondrial damage. In combination with impaired mitophagy, which is characteristic of senescent cells, this could lead to cytosolic mtDNA accumulation and, as a genomic consequence, integrations of mtDNA into nuclear DNA (nDNA), resulting in mitochondrial pseudogenes called numts. Thus, both phenomena could cause structural variants in aging genomes that go beyond epigenetic changes. We therefore compared proliferating and senescent IMR-90 cells in terms of somatic de novo numts and integrations of a non-autonomous composite retrotransposons - the so-called SVA elements—that hijack the retropositional machinery of LINE-1. We applied a subtractive and kinetic enrichment technique using proliferating cell DNA as a driver and senescent genomes as a tester for the detection of nuclear flanks of de novo SVA integrations. Coupled with deep sequencing we obtained a genomic readout for SVA retrotransposition possibly linked to cellular senescence in the IMR-90 model. Furthermore, we compared the genomes of proliferative and senescent IMR-90 cells by deep sequencing or after enrichment of nuclear DNA using AluScan technology. A total of 1,695 de novo SVA integrations were detected in senescent IMR-90 cells, of which 333 were unique. Moreover, we identified a total of 81 de novo numts with perfect identity to both mtDNA and nuclear hg38 flanks. In summary, we present evidence for possible age-dependent structural genomic changes by paralogization that go beyond epigenetic modifications. We hypothesize, that the structural variants we observe potentially impact processes associated with replicative aging of IMR-90 cells.

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Section: Discussionmentioning

confidence: 99%

Generation of somatic de novo structural variation as a hallmark of cellular senescence in human lung fibroblasts

Woronzow,

Möhner,

Remane

et al. 2023

Front. Cell Dev. Biol.

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“…[8][9][10][11][12] ). The frequency of these insertion events increases with stress, aging, and tumorigenesis 8,[13][14][15][16][17] , yet little is known about the enzymes that regulate their transfer to the nucleus. While it is established that nucleases such as EndoG and TREX1 can degrade cytoplasmic DNA in humans to prevent activation of the immune response 18,19 , it remains unclear whether these mechanisms could also play a role in preventing cytoplasmic DNA from causing harmful genome instability.…”

Section: Discussionmentioning

confidence: 99%

“…NUMTs increase during aging across many species 14, 41, 42 . To test the transfer of cytoplasmic DNA to nucleus during aging and a possible role of Nuc1, we first analyzed the lifespan of the strains used to capture DNA sequences at DSB using a microfluidic device.…”

Section: Nuc1 Nuclease Regulates Cdna and Mtdna Insertionsmentioning

confidence: 99%

Yeast EndoG prevents genome instability by degrading cytoplasmic DNA

Yu,

Wang,

Fox

et al. 2023

Preprint

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SummaryIn metazoans release of mitochondrial DNA or retrotransposon cDNA to cytoplasm can cause sterile inflammation and disease. Cytoplasmic nucleases degrade these DNA species to limit inflammation. It remains unknown whether degradation these DNA also prevents nuclear genome instability. To address this question, we decided to identify the nuclease regulating transfer of these cytoplasmic DNA species to the nucleus. We used an amplicon sequencing-based method in yeast enabling analysis of millions of DSB repair products.NuclearmtDNA (NUMTs) and retrotransposon cDNA insertions increase dramatically in nondividing stationary phase cells. Yeast EndoG (Nuc1) nuclease limits insertions of cDNA and transfer of very long mtDNA (>10 kb) that forms unstable circles or rarely insert in the genome, but it promotes formation of short NUMTs (∼45-200 bp). Nuc1 also regulates transfer of cytoplasmic DNA to nucleus in aging or during meiosis. We propose that Nuc1 preserves genome stability by degrading retrotransposon cDNA and long mtDNA, while short NUMTs can originate from incompletely degraded mtDNA. This work suggests that nucleases eliminating cytoplasmic DNA play a role in preserving genome stability.

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“…NUMTs increase during aging across many species 17 , 41 , 42 . To test the transfer of cytoplasmic DNA to nucleus during aging and a possible role of Nuc1, we first analyzed the lifespan of the strains used to capture DNA sequences at DSB using a microfluidic device.…”

Section: Nuc1 Nuclease Regulates Cdna and Mtdna Insertionsmentioning

confidence: 99%

Yeast EndoG prevents genome instability by degrading cytoplasmic DNA

Ira,

Yu,

Wang

et al. 2024

Preprint

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In metazoans release of mitochondrial DNA or retrotransposon cDNA to cytoplasm can cause sterile inflammation and disease 1. Cytoplasmic nucleases degrade these DNA species to limit inflammation 2,3. It remains unknown whether degradation these DNA also prevents nuclear genome instability. To address this question, we decided to identify the nuclease regulating transfer of these cytoplasmic DNA species to the nucleus. We used an amplicon sequencing-based method in yeast enabling analysis of millions of DSB repair products. Nuclear mtDNA (NUMTs) and retrotransposon cDNA insertions increase dramatically in nondividing stationary phase cells. Yeast EndoG (Nuc1) nuclease limits insertions of cDNA and transfer of very long mtDNA (>10 kb) that forms unstable circles or rarely insert in the genome, but it promotes formation of short NUMTs (~45-200 bp). Nuc1 also regulates transfer of cytoplasmic DNA to nucleus in aging or during meiosis. We propose that Nuc1 preserves genome stability by degrading retrotransposon cDNA and long mtDNA, while short NUMTs can originate from incompletely degraded mtDNA. This work suggests that nucleases eliminating cytoplasmic DNA play a role in preserving genome stability.

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Somatic nuclear mitochondrial DNA insertions are prevalent in the human brain and accumulate over time in fibroblasts

Cited by 3 publications

References 95 publications

Generation of somatic de novo structural variation as a hallmark of cellular senescence in human lung fibroblasts

Generation of somatic de novo structural variation as a hallmark of cellular senescence in human lung fibroblasts

Yeast EndoG prevents genome instability by degrading cytoplasmic DNA

Yeast EndoG prevents genome instability by degrading cytoplasmic DNA

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