Extrachromosomal DNA
Multiple forms of extrachromosomal DNA exist, and, while some of these serve important biological functions,[1] they can also play a role in diseases such as cancer.
[7][8][3] ecDNA is considered to be a primary mechanism of gene amplification, resulting in many copies of driver oncogenes and very aggressive cancers.
Although prokaryotic organisms do not possess a membrane-bound nucleus like eukaryotes, they do contain a nucleoid region in which the main chromosome is found.
[13] Naturally occurring circular plasmids can be modified to contain multiple resistance genes and several unique restriction sites, making them valuable tools as cloning vectors in biotechnology.
Plasmid DNA vaccines are genetically engineered to contain a gene which encodes for an antigen or a protein produced by a pathogenic virus, bacterium or other parasites.
Linear plasmids of prokaryotes are found either containing a hairpin loop or a covalently bonded protein attached to the telomeric ends of the DNA molecule.
The adenine-thymine rich hairpin loops of the Borrelia bacteria range in size from 5 kilobase pairs (kb) to over 200 kb[16] and contain the genes responsible for producing a group of major surface proteins, or antigens, on the bacteria that allow it to evade the immune response of its infected host.
[16][17] The long, linear "borgs" that co-occur with a species of archaeon – which may host them and shares many of their genes – could be an unknown form of extrachromosomal DNA structures.
[23] Due to the proximity of the electron transport chain within the mitochondrial inner membrane and the production of reactive oxygen species (ROS), and due to the fact that the mtDNA molecule is not bound by or protected by histones, the mtDNA is more susceptible to DNA damage than nuclear DNA.
However, this code is quite universal and is slightly different in mitochondrial DNA of fungi, animals, protists and plants.
[34] In plants, eccDNA contain repeated sequences similar to those that are found in the centromeric regions of the chromosomes and in repetitive satellite DNA.
[37] A distinct type of extrachromosomal DNA, denoted as ecDNA, is commonly observed in human cancer cells.
The HPV DNA genome undergoes three distinct stages of replication: establishment, maintenance and amplification.
[43] Cells have sensors that can specifically recognize viral DNA such as the Toll-like receptor (TLR) pathway.
TLR9 has evolved to detect CpG DNA commonly found in bacteria and viruses and to initiate the production of IFN (type I interferons ) and other cytokines.
Unlike chromosomes, ecDNA does not contain centromeres and therefore exhibits a non-Mendelian inheritance pattern that gives rise to heterogeneous cell populations.
It is theorized that the uniparental inheritance of mtDNA, which has a high mutation rate, might be a mechanism to maintain the homoplasmy of cytoplasmic DNA.
Small polydispersed DNAs (spcDNAs), a type of eccDNA, are commonly found in conjunction with genome instability.
Extrachromosomal DNA (ecDNA) found in cancer have historically been referred to as Double minute chromosomes (DMs), which present as paired chromatin bodies under light microscopy.
[3] The ecDNA notation encompasses all forms of the large, oncogene-containing, extrachromosomal DNA found in cancer cells.
[22] Loss of the amount of mtDNA present in the mitochondria can lead to a whole subset of diseases known as mitochondrial depletion syndromes (MDDs) which affect the liver, central and peripheral nervous systems, smooth muscle and hearing in humans.
[23] There have been mixed, and sometimes conflicting, results in studies that attempt to link mtDNA copy number to the risk of developing certain cancers.
The malaria parasite (genus Plasmodium), the AIDS-related pathogen (Taxoplasma and Cryptosporidium) are both members of the Apicomplexa group.
[3][8] The most commonly amplified oncogenes in cancer are found on ecDNA and have been shown to be highly dynamic, re-integrating into non-native chromosomes as homogeneous staining regions (HSRs)[51][3] and altering copy numbers and composition in response to various drug treatments.
[54] The circular shape of ecDNA differs from the linear structure of chromosomal DNA in meaningful ways that influence cancer pathogenesis.
[55] Oncogenes encoded on ecDNA have massive transcriptional output, ranking in the top 1% of genes in the entire transcriptome.
