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Frequent somatic transfer of mitochondrial DNA into the nuclear genome of human cancer cells.

ABSTRACT: Mitochondrial genomes are separated from the nuclear genome for most of the cell cycle by the nuclear double membrane, intervening cytoplasm, and the mitochondrial double membrane. Despite these physical barriers, we show that somatically acquired mitochondrial-nuclear genome fusion sequences are present in cancer cells. Most occur in conjunction with intranuclear genomic rearrangements, and the features of the fusion fragments indicate that nonhomologous end joining and/or replication-dependent DNA double-strand break repair are the dominant mechanisms involved. Remarkably, mitochondrial-nuclear genome fusions occur at a similar rate per base pair of DNA as interchromosomal nuclear rearrangements, indicating the presence of a high frequency of contact between mitochondrial and nuclear DNA in some somatic cells. Transmission of mitochondrial DNA to the nuclear genome occurs in neoplastically transformed cells, but we do not exclude the possibility that some mitochondrial-nuclear DNA fusions observed in cancer occurred years earlier in normal somatic cells.

SUBMITTER: Ju YS

PROVIDER: S-EPMC4448678 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Frequent somatic transfer of mitochondrial DNA into the nuclear genome of human cancer cells.

Ju Young Seok YS Tubio Jose M C JM Mifsud William W Fu Beiyuan B Davies Helen R HR Ramakrishna Manasa M Li Yilong Y Yates Lucy L Gundem Gunes G Tarpey Patrick S PS Behjati Sam S Papaemmanuil Elli E Martin Sancha S Fullam Anthony A Gerstung Moritz M Nangalia Jyoti J Green Anthony R AR Caldas Carlos C Borg Åke Å Tutt Andrew A Lee Ming Ta Michael MT van't Veer Laura J LJ Tan Benita K T BK Aparicio Samuel S Span Paul N PN Martens John W M JW Knappskog Stian S Vincent-Salomon Anne A Børresen-Dale Anne-Lise AL Eyfjörd Jórunn Erla JE Myklebost Ola O Flanagan Adrienne M AM Foster Christopher C Neal David E DE Cooper Colin C Eeles Rosalind R Bova Steven G SG Lakhani Sunil R SR Desmedt Christine C Thomas Gilles G Richardson Andrea L AL Purdie Colin A CA Thompson Alastair M AM McDermott Ultan U Yang Fengtang F Nik-Zainal Serena S Campbell Peter J PJ Stratton Michael R MR

Genome research 20150511 6

Mitochondrial genomes are separated from the nuclear genome for most of the cell cycle by the nuclear double membrane, intervening cytoplasm, and the mitochondrial double membrane. Despite these physical barriers, we show that somatically acquired mitochondrial-nuclear genome fusion sequences are present in cancer cells. Most occur in conjunction with intranuclear genomic rearrangements, and the features of the fusion fragments indicate that nonhomologous end joining and/or replication-dependent ...[more]

PMID: 25963125

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Project description:BACKGROUND: The mitochondrial DNA (mtDNA) of the cloned sheep "Dolly" and nine other ovine clones produced by somatic cell nuclear transfer (SCNT) was reported to consist only of recipient oocyte mtDNA without any detectable mtDNA contribution from the nucleus donor cell. In cattle, mouse and pig several or most of the clones showed transmission of nuclear donor mtDNA resulting in mitochondrial heteroplasmy. To clarify the discrepant transmission pattern of donor mtDNA in sheep clones we analysed the mtDNA composition of seven fetuses and five lambs cloned from fetal fibroblasts. RESULTS: The three fetal fibroblast donor cells used for SCNT harboured low mtDNA copy numbers per cell (A: 753 +/- 54, B: 292 +/- 33 and C: 561 +/- 88). The ratio of donor to recipient oocyte mtDNAs was determined using a quantitative amplification refractory mutation system (ARMS) PCR (i.e. ARMS-qPCR). For quantification of SNP variants with frequencies below 0.1% we developed a restriction endonuclease-mediated selective quantitative PCR (REMS-qPCR). We report the first cases (n = 4 fetuses, n = 3 lambs) of recipient oocyte/nuclear donor mtDNA heteroplasmy in SCNT-derived ovine clones demonstrating that there is no species-effect hindering ovine nucleus-donor mtDNA from being transmitted to the somatic clonal offspring. Most of the heteroplasmic clones exhibited low-level heteroplasmy (0.1% to 0.9%, n = 6) indicating neutral transmission of parental mtDNAs. High-level heteroplasmy (6.8% to 46.5%) was observed in one case. This clone possessed a divergent recipient oocyte-derived mtDNA genotype with three rare amino acid changes compared to the donor including one substitution at an evolutionary conserved site. CONCLUSION: Our study using state-of-the-art techniques for mtDNA quantification, like ARMS-qPCR and the novel REMS-qPCR, documents for the first time the transmission of donor mtDNA into somatic sheep clones. MtDNA heteroplasmy was detected in seven of 12 clones tested, whereby all but one case revealed less than 1% mtDNA contribution from the nuclear donor cell suggesting neutral segregation.

Dataset Information

Frequent somatic transfer of mitochondrial DNA into the nuclear genome of human cancer cells.

Publications

Frequent somatic transfer of mitochondrial DNA into the nuclear genome of human cancer cells.

Similar Datasets

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