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.

Sapiens Mitochondrial DNA Genome Circular Long Range Numerical Meta Structures are Highly Correlated with Cancers and Genetic Diseases mtDNA Mutations

“…Indeed, it has been demonstrated [62] that in certain cancer cells, fragments of mtDNA migrate to certain chromosomes of the nuclear genome. Effectively, 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.…”

“…Effectively, 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, Dr Young et al [62] showed that somatically acquired mitochondrial-nuclear genome fusion sequences are present in cancer cells. 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 ( Figure 27) [62].…”

“…Particularly, in the part B of Figure 26 Ju et al [62] represented frequencies of somatic nuclear mtDNA integrations compared to the frequency between autosomes (chromosomal translocation). We note that chromosomes classification (chr 4, 13, 2, …/.... 17 19) are in accord with the chromosomal hierarchy classification that we demonstrate in published paper [44] and in future paper [22].…”

Intracellular mitochondrial DNA transfers to the nucleus in human cancer cells

“…The first systematic study that observed the frequency of SIMTs was performed using large-scale whole-genome sequencing [17 ]. From a total of 587 neoplastic samples (mostly breast cancers), 12 (2%) were found to harbour at least one chimeric mitochondrial-nuclear DNA fusion.…”

“…Throughout these observations, several patterns and mutational processes were suggested for somatic SVs operative in human cells, from simple to complex, such as chromothripsis [12 ], chromoanasynthesis [13 ], chromoplexy [14], and mobile element retrotransposition [15,16], to name a few. Recently, somatic intracellular mtDNA transfers (SIMTs) into the nuclear genome were observed from breast cancers and several cancer cell lines [17 ]. The frequency of SIMTs indicates the presence of a high degree of physical contact between mtDNA and the nuclear genome in human somatic cells.…”