Extrachromosomal DNA (abbreviated ecDNA) is any
DNA that is found off the
chromosome
A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins ar ...
s, either inside or outside the
nucleus
Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to:
* Atomic nucleus, the very dense central region of an atom
*Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA
Nucl ...
of a
cell. Most DNA in an individual
genome
In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ...
is found in
chromosome
A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins ar ...
s contained in the nucleus. Multiple forms of extrachromosomal DNA exist, and, while some of these serve important biological functions,
they can also play a role in diseases, such as ecDNA in cancer.
In
prokaryote
A prokaryote () is a single-celled organism that lacks a nucleus and other membrane-bound organelles. The word ''prokaryote'' comes from the Greek πρό (, 'before') and κάρυον (, 'nut' or 'kernel').Campbell, N. "Biology:Concepts & Con ...
s, nonviral extrachromosomal DNA is primarily found in
plasmid
A plasmid is a small, extrachromosomal DNA molecule within a cell that is physically separated from chromosomal DNA and can replicate independently. They are most commonly found as small circular, double-stranded DNA molecules in bacteria; how ...
s, whereas, in
eukaryote
Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacter ...
s extrachromosomal DNA is primarily found in
organelle
In cell biology, an organelle is a specialized subunit, usually within a cell, that has a specific function. The name ''organelle'' comes from the idea that these structures are parts of cells, as organs are to the body, hence ''organelle,'' th ...
s.
Mitochondrial DNA
Mitochondrial DNA (mtDNA or mDNA) is the DNA located in mitochondria, cellular organelles within eukaryotic cells that convert chemical energy from food into a form that cells can use, such as adenosine triphosphate (ATP). Mitochondrial D ...
is a main source of this extrachromosomal DNA in eukaryotes.
The fact that this organelle contains its own DNA supports the hypothesis that mitochondria originated as bacterial cells engulfed by ancestral eukaryotic cells. Extrachromosomal DNA are often used in research of
replication because they are easy to identify and isolate.
Although
extrachromosomal circular DNA
Extrachromosomal circular DNA (eccDNA) is a type of double-stranded circular DNA structure that was first discovered in 1964 by Alix Bassel and Yasuo Hotta. In contrast to previously identified circular DNA structures (e.g., bacterial plasmids, mit ...
(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.
ecDNA are considered to be a primary mechanism of
gene amplification, resulting in many copies of driver oncogenes and very aggressive cancers.
Extrachromosomal DNA in the
cytoplasm
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...
have been found to be structurally different from nuclear DNA. Cytoplasmic DNA are less
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.
In cancer cells, ecDNA have been shown to be primarily isolated to the nucleus (reviewed in
).
In addition to DNA found outside the nucleus in cells, infection of viral genomes also provides an example of extrachromosomal DNA.
Prokaryotic
Although prokaryotic organisms do not possess a membrane bound nucleus like the eukaryotes, they do contain a
nucleoid region in which the main chromosome is found. Extrachromosomal DNA exists in prokaryotes outside the nucleoid region as circular or linear
plasmids
A plasmid is a small, extrachromosomal DNA molecule within a cell that is physically separated from chromosomal DNA and can replicate independently. They are most commonly found as small circular, double-stranded DNA molecules in bacteria; how ...
. Bacterial plasmids are typically short sequences, consisting of 1 kilobase (kb) to a few hundred kb segments, and contain an origin of replication which allows the plasmid to replicate independently of the bacterial chromosome.
The total number of a particular plasmid within a cell is referred to as the copy number and can range from as few as two copies per cell to as many as several hundred copies per cell.
Circular bacterial plasmids are classified according to the special functions that the genes encoded on the plasmid provide. Fertility plasmids, or f plasmids, allow for
conjugation
Conjugation or conjugate may refer to:
Linguistics
*Grammatical conjugation, the modification of a verb from its basic form
* Emotive conjugation or Russell's conjugation, the use of loaded language
Mathematics
*Complex conjugation, the change ...
to occur whereas resistance plasmids, or r plasmids, contain genes that convey
resistance to a variety of different antibiotics such as ampicillin and tetracycline. There also exist virulence plasmids that contain the genetic elements necessary for bacteria to become pathogenic as well as degradative plasmids that harbor the genes that allow bacteria to degrade a variety of substances such as
aromatic compounds and
xenobiotics
A xenobiotic is a chemical substance found within an organism that is not naturally produced or expected to be present within the organism. It can also cover substances that are present in much higher concentrations than are usual. Natural comp ...
.
Bacterial plasmids can also function in pigment production, nitrogen fixation and the resistance to heavy metals in those bacteria that possess them.
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 applications.
Circular bacterial plasmids are also the basis for the production of
DNA vaccines. Plasmid DNA vaccines are
genetically engineered to contain a gene which encodes for an
antigen
In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune respon ...
or a protein produced by a pathogenic virus, bacterium or other parasites.
Once delivered into the host, the products of the plasmid genes will then stimulate both the
innate immune response
The innate, or nonspecific, immune system is one of the two main immunity strategies (the other being the adaptive immune system) in vertebrates. The innate immune system is an older evolutionary defense strategy, relatively speaking, and is the ...
and the
adaptive immune response
The adaptive immune system, also known as the acquired immune system, is a subsystem of the immune system that is composed of specialized, systemic cells and processes that eliminate pathogens or prevent their growth. The acquired immune system ...
of the host. The plasmids are often coated with some type of
adjuvant In pharmacology, an adjuvant is a drug or other substance, or a combination of substances, that is used to increase the efficacy or potency of certain drugs. Specifically, the term can refer to:
* Adjuvant therapy in cancer management
* Analgesi ...
prior to delivery to enhance the immune response from the host.
Linear bacterial plasmids have been identified in several species of
spirochete bacteria, including members of the genus ''Borrelia'' (to which the pathogen responsible for
Lyme disease
Lyme disease, also known as Lyme borreliosis, is a vector-borne disease caused by the '' Borrelia'' bacterium, which is spread by ticks in the genus '' Ixodes''. The most common sign of infection is an expanding red rash, known as erythema ...
belongs), several species of the
gram positive
In bacteriology, gram-positive bacteria are bacteria that give a positive result in the Gram stain test, which is traditionally used to quickly classify bacteria into two broad categories according to their type of cell wall.
Gram-positive bact ...
soil bacteria of the genus ''Streptomyces'', and in the
gram negative species ''Thiobacillus versutus'', a bacterium that oxidizes sulfur. The linear plasmids of
prokaryote
A prokaryote () is a single-celled organism that lacks a nucleus and other membrane-bound organelles. The word ''prokaryote'' comes from the Greek πρό (, 'before') and κάρυον (, 'nut' or 'kernel').Campbell, N. "Biology:Concepts & Con ...
s 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
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.
The linear plasmids which contain a protein that has been covalently attached to the 5’ end of the DNA strands are known as invertrons and can range in size from 9 kb to over 600 kb consisting of
inverted terminal repeats.
The linear plasmids with a covalently attached protein may assist with bacterial
conjugation
Conjugation or conjugate may refer to:
Linguistics
*Grammatical conjugation, the modification of a verb from its basic form
* Emotive conjugation or Russell's conjugation, the use of loaded language
Mathematics
*Complex conjugation, the change ...
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.
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.
Eukaryotic
Mitochondrial
The
mitochondria
A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used ...
present in eukaryotic cells contain multiple copies of mitochondrial DNA referred to as mtDNA which is housed within the
mitochondrial matrix.
In multicellular animals, including humans, the circular mtDNA chromosome contains 13 genes that encode proteins that are part of the
electron transport chain
An electron transport chain (ETC) is a series of protein complexes and other molecules that transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples ...
and 24 genes that produce RNA necessary for the production of mitochondrial proteins; these genes are broken down into 2
rRNA
Ribosomal ribonucleic acid (rRNA) is a type of non-coding RNA which is the primary component of ribosomes, essential to all cells. rRNA is a ribozyme which carries out protein synthesis in ribosomes. Ribosomal RNA is transcribed from ribos ...
genes and 22
tRNA
Transfer RNA (abbreviated tRNA and formerly referred to as sRNA, for soluble RNA) is an adaptor molecule composed of RNA, typically 76 to 90 nucleotides in length (in eukaryotes), that serves as the physical link between the mRNA and the amino ...
genes.
The size of an animal mtDNA plasmid is roughly 16.6 kb and although it contains genes for tRNA and mRNA synthesis, proteins produced as a result of nuclear genes are still required in order for the mtDNA to replicate or for mitochondrial proteins to be translated.
There is only one region of the mitochondrial chromosome that does not contain a coding sequence and that is the 1 kb region known as the
D-loop to which nuclear regulatory proteins bind.
The number of mtDNA molecules per mitochondria 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.
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.
In cases where mtDNA damage does occur, the DNA can either be repaired via
base excision repair
Base excision repair (BER) is a cellular mechanism, studied in the fields of biochemistry and genetics, that repairs damaged DNA throughout the cell cycle. It is responsible primarily for removing small, non-helix-distorting base lesions from ...
pathways, or the damaged mtDNA molecule is destroyed (without causing damage to the mitochondrion since there are multiple copies of mtDNA per mitochondrion).
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 universal nature of the code is not the case with mitochondrial DNA found in fungi, animals, protists and plants.
While most of the 3-base sequences in the mtDNA of these organisms do code for the same amino acids as those of the nuclear genetic code, there are some mtDNA sequences that code for amino acids different from those of their nuclear DNA counterparts.
The coding differences are thought to be a result of chemical modifications in the
transfer RNAs that interact with the
messenger RNAs produced as a result of
transcribing the mtDNA sequences.
Chloroplast
Eukaryotic
chloroplasts, as well as the other plant
plastids, also contain extrachromosomal DNA molecules. Most chloroplasts house all of their genetic material in a single ringed chromosome, however in some species there is evidence of multiple smaller ringed
plasmids
A plasmid is a small, extrachromosomal DNA molecule within a cell that is physically separated from chromosomal DNA and can replicate independently. They are most commonly found as small circular, double-stranded DNA molecules in bacteria; how ...
.
A recent theory that questions the current standard model of ring shaped chloroplast DNA (cpDNA), suggests that cpDNA may more commonly take a linear shape. A single molecule of cpDNA can contain anywhere from 100-200 genes
and varies in size from species to species. The size of cpDNA in higher plants is around 120–160 kb.
The genes found on the cpDNA code for mRNAs that are responsible for producing necessary components of the
photosynthetic pathway as well as coding for tRNAs,
rRNA
Ribosomal ribonucleic acid (rRNA) is a type of non-coding RNA which is the primary component of ribosomes, essential to all cells. rRNA is a ribozyme which carries out protein synthesis in ribosomes. Ribosomal RNA is transcribed from ribos ...
s,
RNA polymerase subunits, and
ribosomal protein subunits.
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.
Circular
Extrachromosomal circular DNA (eccDNA) are present in all
eukaryotic cells
Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bact ...
, are usually derived from genomic DNA, and consist of repetitive sequences of DNA found in both coding and non-coding regions of chromosomes. EccDNA can vary in size from less than 2000 base pairs to more than 20,000 base pairs.
In plants, eccDNA contain repeated sequences similar to those that are found in the
centromeric
The centromere links a pair of sister chromatids together during cell division. This constricted region of chromosome connects the sister chromatids, creating a short arm (p) and a long arm (q) on the chromatids. During mitosis, spindle fibers ...
regions of the chromosomes and in repetitive satellite DNA.
In animals, eccDNA molecules have been shown to contain repetitive sequences that are seen in
satellite DNA,
5S ribosomal DNA and
telomere
A telomere (; ) is a region of repetitive nucleotide sequences associated with specialized proteins at the ends of linear chromosomes. Although there are different architectures, telomeres, in a broad sense, are a widespread genetic feature mos ...
DNA.
Certain organisms, such as yeast, rely on chromosomal DNA replication to produce eccDNA
whereas eccDNA formation can occur in other organisms, such as mammals, independently of the replication process.
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.
A distinct type of extrachromosomal DNA, denoted as
ecDNA, is commonly observed in human cancer cells.
ecDNA found in cancer cells contain one or more genes that confer a selective advantage. ecDNA are much larger than eccDNA, and are visible by light microscopy. ecDNA in cancers generally range in size from 1-3 MB and beyond.
Large ecDNA molecules have been found in the nuclei of human cancer cells and are shown to carry many copies of driver
oncogenes
An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels. , 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
Paul S. Mischel (born July 13, 1962) is an American physician-scientist whose laboratory has made pioneering discoveries in the pathogenesis of human cancer. He is currently a Professor and Vice Chair of Research for the Department of Pathology and ...
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.
Viral
Viral DNA are an example of extrachromosomal DNA. Understanding viral genomes is very important for understanding the evolution and mutation of the virus. Some viruses, such as
HIV and
oncogenic viruses, incorporate their own DNA into the genome of the host cell.
Viral genomes can be made up of single stranded DNA (
ssDNA), double stranded DNA (
dsDNA) and can be found in both linear and circular form.
One example of infection of a virus constituting as extrachromosomal DNA is the human papillomavirus (
HPV
Human papillomavirus infection (HPV infection) is caused by a DNA virus from the ''Papillomaviridae'' family. Many HPV infections cause no symptoms and 90% resolve spontaneously within two years. In some cases, an HPV infection persists and res ...
). The HPV DNA genome undergoes three distinct stages of replication: establishment, maintenance and amplification. HPV infects
epithelial
Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellu ...
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.
Recognition by host cell
Cells can recognize foreign cytoplasmic DNA. Understanding the recognition pathways has implications towards prevention and treatment of diseases.
Cells have sensors that can specifically recognize viral DNA such as the Toll-like receptor (TLR) pathway.
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 (
pathogen-associated molecular patterns). PAMPs are known to be potent activators of
innate immune signaling. There are approximately 10 human
Toll-Like Receptor
Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single-pass membrane-spanning receptors usually expressed on sentinel cells such as macrophages and dendritic cells, that recognize ...
s (TLRs). Different TLRs in human detect different PAMPS:
lipopolysaccharide
Lipopolysaccharides (LPS) are large molecules consisting of a lipid and a polysaccharide that are bacterial toxins. They are composed of an O- antigen, an outer core, and an inner core all joined by a covalent bond, and are found in the out ...
s by
TLR4, viral
dsRNA by
TLR3
Toll-like receptor 3 (TLR3) also known as CD283 (cluster of differentiation 283) is a protein that in humans is encoded by the ''TLR3'' gene. TLR3 is a member of the toll-like receptor family of pattern recognition receptors of the innate imm ...
, viral ssRNA by
TLR7
Toll-like receptor 7, also known as TLR7, is a protein that in humans is encoded by the ''TLR7'' gene. Orthologs are found in mammals and birds. It is a member of the toll-like receptor (TLR) family and detects single stranded RNA.
Function ...
/
TLR8, viral or bacterial unmethylated DNA by
TLR9
Toll-like receptor 9 is a protein that in humans is encoded by the ''TLR9'' gene. TLR9 has also been designated as CD289 (cluster of differentiation 289). It is a member of the toll-like receptor (TLR) family. TLR9 is an important receptor expre ...
. TLR9 has evolved to detect
CpG DNA commonly found in bacteria and viruses and to initiate the production of
IFN
Interferons (IFNs, ) are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten thei ...
(type I interferons ) and other
cytokines.
Inheritance
Inheritance
Inheritance is the practice of receiving private property, titles, debts, entitlements, privileges, rights, and obligations upon the death of an individual. The rules of inheritance differ among societies and have changed over time. Of ...
of extrachromosomal DNA differs from the inheritance of nuclear DNA found in chromosomes. Unlike chromosomes,
ecDNA does not contain
centromere
The centromere links a pair of sister chromatids together during cell division. This constricted region of chromosome connects the sister chromatids, creating a short arm (p) and a long arm (q) on the chromatids. During mitosis, spindle fibers ...
s and therefore exhibits a non-Mendelian inheritance pattern that gives rise to heterogeneous cell populations. In humans, virtually all of the cytoplasm is inherited from the egg of the mother.
For this reason, organelle DNA, including mtDNA, is inherited from the mother.
Mutations in mtDNA or other cytoplasmic DNA will also be inherited from the mother. This
uniparental inheritance Uniparental inheritance is a non-Mendelian form of inheritance that consists of the transmission of genotypes from one parental type to all progeny. That is, all the genes in offspring will originate from only the mother or only the father. This phe ...
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.
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.
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
A retrovirus is a type of virus that inserts a DNA copy of its RNA genome into the DNA of a host cell that it invades, thus changing the genome of that cell. Once inside the host cell's cytoplasm, the virus uses its own reverse transcriptas ...
-like DNA elements, and transposable elements in the genome. They are thought to be the products of gene rearrangements.
Extrachromosomal DNA (
ecDNA) found in cancer have historically been referred to as
Double minute Double minutes are small fragments of extrachromosomal DNA, which have been observed in a large number of human tumors including breast, lung, ovary, colon, and most notably, neuroblastoma. They are a manifestation of gene amplification as a result ...
chromosomes (DMs), which present as paired
chromatin
Chromatin is a complex of DNA and protein found in eukaryote, eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important ...
bodies under
light microscopy
Microscopy is the technical field of using microscopes to view objects and areas of objects that cannot be seen with the naked eye (objects that are not within the resolution range of the normal eye). There are three well-known branches of micr ...
. Double minute chromosomes represent ~30% of the cancer-containing spectrum of ecDNA, including single bodies and have been found to contain identical gene content as single bodies.
The ecDNA notation encompasses all forms of the large, oncogene-containing, extrachromosomal DNA found in cancer cells. This type of ecDNA is commonly seen in
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
cells of various histologies, but virtually never in normal cells.
ecDNA are thought to be produced through
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.
Mitochondrial DNA can play a role in the onset of disease in a variety of ways.
Point mutations in or alternative
gene arrangements of mtDNA have been linked to several diseases that affect the heart,
central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...
,
endocrine system
The endocrine system is a messenger system comprising feedback loops of the hormones released by internal glands of an organism directly into the circulatory system, regulating distant target organs. In vertebrates, the hypothalamus is th ...
, gastrointestinal tract, eye, and kidney.
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.
There have been mixed, and sometimes conflicting, results in studies that attempt to link mtDNA copy number to the risk of developing certain cancers. Studies have been conducted that show an association between both increased and decreased mtDNA levels and the increased risk of developing
breast cancer
Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or ...
. A positive association between increased mtDNA levels and an increased risk for developing
kidney tumors has been observed but there does not appear to be a link between mtDNA levels and the development of
stomach cancer
Stomach cancer, also known as gastric cancer, is a cancer that develops from the lining of the stomach. Most cases of stomach cancers are gastric carcinomas, which can be divided into a number of subtypes, including gastric adenocarcinomas. Ly ...
.
Extrachromosomal DNA is found in
Apicomplexa, which is a group of
protozoa
Protozoa (singular: protozoan or protozoon; alternative plural: protozoans) are a group of single-celled eukaryotes, either free-living or parasitic, that feed on organic matter such as other microorganisms or organic tissues and debris. Histo ...
. The
malaria
Malaria is a mosquito-borne infectious disease that affects humans and other animals. Malaria causes symptoms that typically include fever, tiredness, vomiting, and headaches. In severe cases, it can cause jaundice, seizures, coma, or death. ...
parasite (genus Plasmodium), the
AIDS
Human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV), a retrovirus. Following initial infection an individual ma ...
-related pathogen (
Taxoplasma and
Cryptosporidium) are both members of the Apicomplexa group. Mitochondrial DNA (mtDNA) was found in the malaria parasite.
There are two forms of extrachromosomal DNA found in the malaria parasites. One of these is 6-kb linear DNA and the second is 35-kb circular DNA. These DNA molecules have been researched as potential
nucleotide
Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecu ...
target sites for
antibiotics
An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and preventio ...
.
Role of ecDNA in cancer
Gene amplification is among the most common mechanisms of
oncogene activation. Gene amplifications in cancer are often on extrachromosomal, circular elements.
One of the primary functions of
ecDNA in cancer is to enable the tumor to rapidly reach high
copy numbers, while also promoting rapid, massive cell-to-cell
genetic heterogeneity.
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)
and altering copy numbers and composition in response to various drug treatments.
The circular shape of ecDNA differs from the linear structure of chromosomal DNA in meaningful ways that influence cancer
pathogenesis.
Oncogenes encoded on ecDNA have massive transcriptional output, ranking in the top 1% of
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
s in the entire
transcriptome
The transcriptome is the set of all RNA transcripts, including coding and non-coding, in an individual or a population of cells. The term can also sometimes be used to refer to all RNAs, or just mRNA, depending on the particular experiment. The t ...
. In contrast to bacterial
plasmid
A plasmid is a small, extrachromosomal DNA molecule within a cell that is physically separated from chromosomal DNA and can replicate independently. They are most commonly found as small circular, double-stranded DNA molecules in bacteria; how ...
s or mitochondrial DNA, ecDNA are chromatinized, containing high levels of active histone marks, but a paucity of repressive histone marks. The ecDNA
chromatin
Chromatin is a complex of DNA and protein found in eukaryote, eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important ...
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.
Spacially, ecDNA hubs could cause intermolecular enhancer–gene interactions to promote oncogene overexpression.
References
Further reading
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{{DEFAULTSORT:Extrachromosomal Dna
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