Extrachromosomal DNA

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Extrachromosomal DNA (abbreviated ecDNA) is any DNA that is found off the chromosomes, either inside or outside the nucleus of a cell. Most DNA in an individual genome is found in chromosomes contained in the nucleus. 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.[2][3][4]

In prokaryotes, nonviral extrachromosomal DNA is primarily found in plasmids, whereas, in eukaryotes extrachromosomal DNA is primarily found in organelles.[1] Mitochondrial DNA is a main source of this extrachromosomal DNA in eukaryotes.[5] The fact that this organelle contains its own DNA supports the hypothesis that mitochondria originated as bacterial cells engulfed by ancestral eukaryotic cells.[6] Extrachromosomal DNA is often used in research into replication because it is easy to identify and isolate.[1]

Although extrachromosomal circular DNA (eccDNA) is found in normal eukaryotic cells, extrachromosomal DNA (ecDNA) is a distinct entity that has been identified in the nuclei of cancer cells and has been shown to carry many copies of driver oncogenes.[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.  

Extrachromosomal DNA in the

methylated than DNA found within the nucleus. It was also confirmed that the sequences of cytoplasmic DNA were different from nuclear DNA in the same organism, showing that cytoplasmic DNAs are not simply fragments of nuclear DNA.[9] In cancer cells, ecDNA have been shown to be primarily isolated to the nucleus (reviewed in [2]
).

In addition to DNA found outside the nucleus in cells, infection by viral genomes also provides an example of extrachromosomal DNA.

Prokaryotic

E. coli

Although prokaryotic organisms do not possess a membrane-bound nucleus like eukaryotes, they do contain a

xenobiotics.[12] Bacterial plasmids can also function in pigment production, nitrogen fixation and the resistance to heavy metals.[13]

Naturally occurring circular plasmids can be modified to contain multiple resistance genes and several unique

adaptive immune response of the host. The plasmids are often coated with some type of adjuvant prior to delivery to enhance the immune response from the host.[15]

Linear bacterial plasmids have been identified in several species of

inverted terminal repeats.[16] The linear plasmids with a covalently attached protein may assist with bacterial conjugation and integration of the plasmids into the genome. These types of linear plasmids represent the largest class of extrachromosomal DNA as they are not only present in certain bacterial cells, but all linear extrachromosomal DNA molecules found in eukaryotic cells also take on this invertron structure with a protein attached to the 5’ end.[16][17]

The long, linear "

archaeon – which may host them and shares many of their genes – could be an unknown form of extrachromosomal DNA structures.[18][19][20]

Eukaryotic

Mitochondrial

Human mitochondrial DNA showing the 37 genes

tRNA genes.[22] The size of an animal mtDNA plasmid is roughly 16.6 kb and, although it contains genes for tRNA and mRNA synthesis, proteins coded for by nuclear genes are still required for the mtDNA to replicate or for mitochondrial proteins to be translated.[23] There is only one region of the mitochondrial chromosome that does not contain a coding sequence, the 1 kb region known as the D-loop to which nuclear regulatory proteins bind.[22] The number of mtDNA molecules per mitochondrion varies from species to species, as well as between cells with different energy demands. For example, muscle and liver cells contain more copies of mtDNA per mitochondrion than blood and skin cells do.[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.[24] In cases where mtDNA damage does occur, the DNA can either be repaired via base excision repair pathways, or the damaged mtDNA molecule is destroyed (without causing damage to the mitochondrion since there are multiple copies of mtDNA per mitochondrion).[25]

The standard genetic code by which nuclear genes are translated is universal, meaning that each 3-base sequence of DNA codes for the same amino acid regardless of what species from which the DNA comes. However, this code is quite universal and is slightly different in mitochondrial DNA of fungi, animals, protists and plants.[21] While most of the 3-base sequences (codons) in the mtDNA of these organisms do code for the same amino acids as those of the nuclear genetic code, a few are different.

Coding differences found in the mtDNA sequences of various organisms
Genetic code Translation table DNA codon involved RNA codon involved Translation with this code Comparison with the universal code
Vertebrate mitochondrial 2 AGA AGA Ter (*) Arg (R)
AGG AGG Ter (*) Arg (R)
ATA AUA Met (M) Ile (I)
TGA UGA Trp (W) Ter (*)
Yeast mitochondrial 3 ATA AUA Met (M) Ile (I)
CTT CUU Thr (T) Leu (L)
CTC CUC Thr (T) Leu (L)
CTA CUA Thr (T) Leu (L)
CTG CUG Thr (T) Leu (L)
TGA UGA Trp (W) Ter (*)
CGA CGA absent Arg (R)
CGC CGC absent Arg (R)
Mold, protozoan, and coelenterate mitochondrial 4 and 7 TGA UGA Trp (W) Ter (*)
Invertebrate mitochondrial 5 AGA AGA Ser (S) Arg (R)
AGG AGG Ser (S) Arg (R)
ATA AUA Met (M) Ile (I)
TGA UGA Trp (W) Ter (*)
Echinoderm and flatworm mitochondrial 9 AAA AAA Asn (N) Lys (K)
AGA AGA Ser (S) Arg (R)
AGG AGG Ser (S) Arg (R)
TGA UGA Trp (W) Ter (*)
Ascidian mitochondrial 13 AGA AGA Gly (G) Arg (R)
AGG AGG Gly (G) Arg (R)
ATA AUA Met (M) Ile (I)
TGA UGA Trp (W) Ter (*)
Alternative flatworm mitochondrial 14 AAA AAA Asn (N) Lys (K)
AGA AGA Ser (S) Arg (R)
AGG AGG Ser (S) Arg (R)
TAA UAA Tyr (Y) Ter (*)
TGA UGA Trp (W) Ter (*)
Chlorophycean mitochondrial 16 TAG UAG Leu (L) Ter (*)
Trematode mitochondrial 21 TGA UGA Trp (W) Ter (*)
ATA AUA Met (M) Ile (I)
AGA AGA Ser (S) Arg (R)
AGG AGG Ser (S) Arg (R)
AAA AAA Asn (N) Lys (K)
Scenedesmus obliquus mitochondrial 22 TCA UCA Ter (*) Ser (S)
TAG UAG Leu (L) Ter (*)
Thraustochytrium mitochondrial 23 TTA UUA Ter (*) Leu (L)
Pterobranchia mitochondrial 24 AGA AGA Ser (S) Arg (R)
AGG AGG Lys (K) Arg (R)
TGA UGA Trp (W) Ter (*)
Amino acids
 biochemical properties 		nonpolar polar basic acidic Termination: stop codon

The coding differences are thought to be a result of chemical modifications in the

transcribing the mtDNA sequences.[26]

Chloroplast

Eukaryotic

rRNAs, RNA polymerase subunits, and ribosomal protein subunits.[32] Like mtDNA, cpDNA is not fully autonomous and relies upon nuclear gene products for replication and production of chloroplast proteins. Chloroplasts contain multiple copies of cpDNA and the number can vary not only from species to species or cell type to cell type, but also within a single cell depending upon the age and stage of development of the cell. For example, cpDNA content in the chloroplasts of young cells, during the early stages of development where the chloroplasts are in the form of indistinct proplastids, are much higher than those present when that cell matures and expands, containing fully mature plastids.[33]

Circular

Main article: Extrachromosomal circular DNA

Extrachromosomal circular DNA (eccDNA) are present in all

5S ribosomal DNA and telomere DNA.[34] Certain organisms, such as yeast, rely on chromosomal DNA replication to produce eccDNA[35] whereas eccDNA formation can occur in other organisms, such as mammals, independently of the replication process.[36] The function of eccDNA have not been widely studied, but it has been proposed that the production of eccDNA elements from genomic DNA sequences add to the plasticity of the eukaryotic genome and can influence genome stability, cell aging and the evolution of chromosomes.[37]

A distinct type of extrachromosomal DNA, denoted as ecDNA, is commonly observed in human cancer cells.

oncogenes
, which are transcribed in tumor cells. Based on this evidence it is thought that ecDNA contributes to cancer growth.

Specialized tools exist that allow ecDNA to be identified, such as

  • software developed by Paul Mischel and Vineet Bafna that allows ecDNA to be identified in microscopic images
  • "Circle-Seq, a method for physically isolating ecDNA from cells, removing any remaining linear DNA with enzymes, and sequencing the circular DNA that remains", developed by Birgitte Regenberg and her team at the University of Copenhagen.[38]

Viral

Viral DNA are an example of extrachromosomal DNA. Understanding viral genomes is very important for understanding the evolution and mutation of the virus.

dsDNA) and can be found in both linear and circular form.[41]

One example of infection of a virus constituting as extrachromosomal DNA is the human papillomavirus (

epithelial cells in the anogenital tract and oral cavity. Normally, HPV is detected and cleared by the immune system. The recognition of viral DNA is an important part of immune responses. For this virus to persist, the circular genome must be replicated and inherited during cell division.[42]

Recognition by host cell

Cells can recognize foreign cytoplasmic DNA. Understanding the recognition pathways has implications towards prevention and treatment of diseases.[43] Cells have sensors that can specifically recognize viral DNA such as the Toll-like receptor (TLR) pathway.[44]

The Toll Pathway was recognized, first in insects, as a pathway that allows certain cell types to act as sensors capable of detecting a variety of bacterial or viral genomes and PAMPS (

cytokines.[44]

Inheritance

Mitochondrial inheritance in humans: the mtDNA and its mutations are maternally transmitted.

Mutations in mtDNA or other cytoplasmic DNA will also be inherited from the mother. This uniparental inheritance is an example of non-Mendelian inheritance. Plants also show uniparental mtDNA inheritance. Most plants inherit mtDNA maternally with one noted exception being the redwood Sequoia sempervirens that inherit mtDNA paternally.[46]

There are two theories why the paternal

mtDNA is rarely transmitted to the offspring. One is simply the fact that paternal mtDNA is at such a lower concentration than the maternal mtDNA and thus it is not detectable in the offspring. A second, more complex theory, involves the digestion of the paternal mtDNA to prevent its inheritance. 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.[46]

Clinical significance

Sometimes called EEs, extrachromosomal elements, have been associated with

genomic instability in eukaryotes. Small polydispersed DNAs (spcDNAs), a type of eccDNA, are commonly found in conjunction with genome instability. SpcDNAs are derived from repetitive sequences such as satellite DNA, retrovirus
-like DNA elements, and transposable elements in the genome. They are thought to be the products of gene rearrangements.

Extrachromosomal DNA (

double-strand breaks in chromosomes or over-replication of DNA in an organism. Studies show that in cases of cancer and other genomic instability, higher levels of EEs can be observed.[5]

Mitochondrial DNA can play a role in the onset of disease in a variety of ways.

kidney tumors has been observed but there does not appear to be a link between mtDNA levels and the development of stomach cancer.[47]

Extrachromosomal DNA is found in

antibiotics.[49]

Role of ecDNA in cancer

copy numbers, while also promoting rapid, massive cell-to-cell genetic heterogeneity.[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.[52][7][53]

ecDNA is responsible for a large number of the more advanced and most serious cancers, as well as for the resistance to anti-cancer drugs.[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.  In contrast to bacterial plasmids or mitochondrial DNA, ecDNA are chromatinized, containing high levels of active histone marks, but a paucity of repressive histone marks. The ecDNA chromatin architecture lacks the higher-order compaction that is present on chromosomal DNA and is among the most accessible DNA in the entire cancer genome.

EcDNAs could be clustered together within the nucleus, which can be referred to as ecDNA hubs.[56] Spacially, ecDNA hubs could cause intermolecular enhancer–gene interactions to promote oncogene overexpression.

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Further reading

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