Extrachromosomal DNA

Extrachromosomal DNA (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.

ecDNA they can also play a role in diseases such as cancer.

In eukaryotes extrachromosomal DNA is primarily found in organelles.

Mitochondrial DNA is a main source of this extrachromosomal DNA in eukaryotes.

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.

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 cytoplasm is structurally different from nuclear DNA. 

Cytoplasmic DNAs are not simply fragments of nuclear DNA.

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

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 or a protein produced by a pathogenic virus, bacterium or other parasites.

The products of the plasmid genes will then stimulate both the innate immune response and the adaptive immune response of the host. 

Linear bacterial plasmids have been identified in several species of spirochete bacteria, including Borrelia, several species of the gram positive soil bacteria of the genus Streptomyces, and in the gram negative species Thiobacillus versutus, a bacterium that oxidizes sulfur. 

Mitochondria present in eukaryotic cells contain multiple copies of mitochondrial DNA (mtDNA) in the mitochondrial matrix.

The circular mtDNA chromosome contains 13 genes that encode proteins that are part of the electron transport chain and 24 genes for other mitochondrial proteins; these genes are broken down into 2 rRNA genes and 22 tRNA genes.

The number of mtDNA molecules per mitochondrion varies 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.

mtDNA is more susceptible to DNA damage than nuclear DNA due to its proximity of the electron transport chain within the mitochondrial inner membrane and the production of reactive oxygen species, and the mtDNA molecule is not bound by or protected by histones.

Extrachromosomal circular DNA (eccDNA) are present in all eukaryotic cells. 

The eccDNA are usually derived from genomic DNA, and consist of repetitive sequences of DNA found in both coding and non-coding regions of chromosomes. 

The extrachromosomal circular DNA (eccDNA) can vary in size from less than 2000 base pairs to more than 20,000 base pairs.

The function of eccDNA is proposed to be the production of eccDNA elements from genomic DNA sequences,which 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. 

Large ecDNA molecules have been found in the nuclei of human cancer cells and are shown to carry many copies of driver oncogenes, which are transcribed in tumor cells. 

It is held that ecDNA contributes to cancer growth.

Specialized tools exist that allow ecDNA to be identified.

“Circle-Seq, a method for physically isolating ecDNA from cells.

Viral DNA are an example of extrachromosomal DNA. 

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.

The human papillomavirus (HPV) infection constitutes as an extrachromosomal DNA.

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.

Cells can recognize foreign cytoplasmic DNA.

Cells have sensors that can specifically recognize viral DNA such as the Toll-like receptor (TLR) pathway.

The Toll Pathway 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).

PAMPs are known to be potent activators of innate immune signaling. 

There are approximately 10 human Toll-Like Receptors (TLRs). 

Different TLRs in human detect different PAMPS: detect CpG DNA commonly found in bacteria and viruses and to initiate the production of IFN (type I interferons ) and other cytokines.

Mitochondria (mtDNA)and its mutations are maternally transmitted.

Inheritance of extrachromosomal DNA differs from the inheritance of nuclear DNA found in chromosomes. 

ecDNA does not contain centromeres and therefore exhibits a non-Mendelian inheritance pattern that gives rise to heterogeneous cell populations. 

Virtually all of the cytoplasm in cells is inherited from the egg of the mother: organelle DNA, including mtDNA, is inherited from the mother. 

Mutations in mtDNA or other cytoplasmic DNA will also be inherited from the mother in a non-Mendelian inheritance fashion.

Extrachromosomal DNA (ecDNA) found in cancer have historically been referred to as double minute chromosomes (DMs), are present as paired chromatin bodies under light microscopy. 

Double minute chromosomes represent approximately 30% of the cancer-containing spectrum of ecDNA.

The ecDNA encompasses all forms of the large, oncogene-containing, extrachromosomal DNA found in cancer cells.  

This type of ecDNA is commonly seen in cancer cells virtually never in normal cells.

ecDNA is produced through double-strand breaks in chromosomes or over-replication of DNA in an organism. 

Incases of cancer and other genomic instability, higher levels of EEs can be observed.

Mitochondrial DNA can play a role in the onset of diseases.

 Point mutations in or alternative gene arrangements of mtDNA have been linked to several diseases that affect the heart, central nervous system, endocrine system, 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.

Studies have been conducted that show an association between both increased and decreased mtDNA levels and the increased risk of developing breast cancer. 

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.

Gene amplification is among the most common mechanisms of oncogene activation, and in  cancer are often on extrachromosomal, circular elements.

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.

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.

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 genes


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