Extrachromosomal circular DNA

Extrachromosomal circular DNA (eccDNA) are circular DNA found in human, plant and animal cells in addition to chromosomal DNA. eccDNA originate from chromosomal DNA and can be from 50 base pairs to several mega-base pairs in length and encode regulatory elements and several full genes.

eccDNA was first discovered in 1964 by Alix Bassel and Yasuo Hoota[1] in wheat nuclei and boar sperm.[2] Since then, eccDNA has been observed in almost all organisms from plants, yeast, C. elegans, frogs, mice, chicken, birds, and humans.[3][4][5][6][7][8][9] eccDNA molecules originate in normal cells and are a by product of programmed DNA recombination events; such as V(D)J recombination.[10][9] Moreover, eccDNA production seems to be cell-type specific in somatic cells.[9]

Role in cancer

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. They are a manifestation of gene amplification during the development of tumors, which give the cells selective advantages for growth and survival. Double minutes, like actual chromosomes, are composed of chromatin and replicate in the nucleus of the cell during cell division. 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.[11] Double minute chromosomes represent ~30% of the cancer-containing spectrum of ecDNA, including single bodies,[11] and have been found to contain identical gene content as single bodies. The ecDNA notation encompasses all forms of the large gene-containing extrachromosomal DNA found in cancer cells. This type of ecDNA is commonly seen in cancer cells of various histologies, but virtually never in normal tissue.[11] ecDNA are thought to be produced through double-strand breaks in chromosomes or over replication of DNA in an organism.[12]

The circular shape of ecDNA differs from the linear structure of chromosomal DNA in meaningful ways that influence cancer pathogenesis.[13][14] 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.

Much effort has been focussed on structure and role of ecDNA in cancer tumors, there are new efforts to develop therapeutics that potentially target ecDNA. Boundless Bio, Inc. is a private biotechnology company focused on the discovery and development of cancer therapeutics that inhibit the formation and propagation of extrachromosomal DNA. To further research on published therapeutic paradigms,[15][14][11] the company was founded in 2018 by scientists Paul Mischel, Roel Verhaak, Prashant Mali, Vineet Bafna, Howard Chang, and Ben Cravatt. Boundless Bio is a Delaware corporation headquartered in La Jolla, California. The company’s core technology platform is based on the discoveries of extrachromosomal DNA and their involvement in driving copy number amplification of oncogenes in cancer. The founders have described the work and mission to be the foremost biopharma company interrogating extrachromosomal DNA (ecDNA) biology to deliver transformative therapies to patients with previously intractable cancer.[16][17][13]

See also

References
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  14. Wu S, Turner KM, Nguyen N, Raviram R, Erb M, Santini J, et al. (November 2019). "Circular ecDNA promotes accessible chromatin and high oncogene expression". Nature. 575 (7784): 699–703. Bibcode:2019Natur.575..699W. doi:10.1038/s41586-019-1763-5. PMC 7094777. PMID 31748743.
  15. Nathanson, David A.; Gini, Beatrice; Mottahedeh, Jack; Visnyei, Koppany; Koga, Tomoyuki; Gomez, German; Eskin, Ascia; Hwang, Kiwook; Wang, Jun; Masui, Kenta; Paucar, Andres (2014-01-03). "Targeted therapy resistance mediated by dynamic regulation of extrachromosomal mutant EGFR DNA". Science. 343 (6166): 72–76. doi:10.1126/science.1241328. ISSN 1095-9203. PMC 4049335. PMID 24310612.
  16. Research, American Association for Cancer (2020-01-06). "Circular DNA Throws Gene Regulation for a Loop". Cancer Discovery. 10: 170. doi:10.1158/2159-8290.CD-ND2019-016. ISSN 2159-8274. PMID 31907167.
  17. "Biotech startup hopes to disarm cancer by targeting a genetic bandolier". STAT. 2019-09-19. Retrieved 2020-06-12.

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