Extrachromosomal circular DNA
[8][9] In 1964, Bassel and Hotta published their initial discovery of eccDNA that they made while researching Franklin Stahl’s chromosomal theory.
[27] As research has continued, different subtypes of extrachromosomal circular DNA have been identified that are not double minutes (e.g., microDNA).
Researchers have hypothesized that eccDNA may contribute to the expression of different isoforms of a gene by interfering with or promoting the transcription of specific exons.
[33] There are multiple proposed mechanisms for eccDNA formation: (1) replication slippage creates a loop on the template strand that is then excised and ligated into a circle leaving a microdeletion on the chromosome, (2) replication slippage creates a loop in the product strand that is excised and ligated into a circle that does not generate a microdeletion in the chromosome, (3) the ODERA mechanism of eccDNA formation, and (4) a double stranded break in a repeat region is repaired by homologous recombination, during which the fragment forms a circle and the chromosome suffers a microdeletion[1] Research conducted in 2021 demonstrated that apoptotic cells are a source of eccDNAs; this was concluded on account of the study showing that apoptotic DNA fragmentation (ADF) is a prerequisite for eccDNA formation through purification methods.
[31] Some known functions of eccDNA include contributions to intercellular genetic heterogeneity in tumors, and more specifically the amplification of oncogenes and drug-resistant genes.
Overall, eccDNA has been linked to cancer and drug resistance, aging, gene compensation,[1] and for this reason it continues to be a significant topic of discussion.
A subtype of eccDNA, such as ecDNA, ribosomal DNA locus (Extrachromosomal rDNA circle), and double minutes have been associated with genomic instability.
Double minute ecDNAs are fragments of extrachromosomal DNA, which were originally observed in a large number of human tumors including breast, lung, ovary, colon, and most notably, neuroblastoma.
Unlike typical chromosomes, they are composed of circular fragments of DNA, up to only a few million base pairs in size and contain no centromere or telomere.
Double minute chromosomes (DMs), which present as paired chromatin bodies under light microscopy, have been shown to be a subset of ecDNA.
The ecDNA notation encompasses all forms of the large gene-containing extrachromosomal DNA found in cancer cells.
[40] The circular shape of ecDNA differs from the linear structure of chromosomal DNA in meaningful ways that influence cancer pathogenesis.
[41][30] Oncogenes encoded on ecDNA have massive transcriptional output, ranking in the top 1% of genes in the entire transcriptome.
