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Review
. 2021 Sep 9:8:693641.
doi: 10.3389/fvets.2021.693641. eCollection 2021.

Extrachromosomal Circular DNA: Category, Biogenesis, Recognition, and Functions

Xiukai Cao  1 , Shan Wang  2 , Ling Ge  2 , Weibo Zhang  2 , Jinlin Huang  3 , Wei Sun  1   2
Affiliations
Review

Extrachromosomal Circular DNA: Category, Biogenesis, Recognition, and Functions

Xiukai Cao et al. Front Vet Sci. .

Erratum in

Abstract

Extrachromosomal circular DNA (eccDNA), existing as double-stranded circular DNA, is derived and free from chromosomes. It is common in eukaryotes but has a strong heterogeneity in count, length, and origin. It has been demonstrated that eccDNA could function in telomere and rDNA maintenance, aging, drug resistance, tumorigenesis, and phenotypic variations of plants and animals. Here we review the current knowledge about eccDNA in category, biogenesis, recognition, and functions. We also provide perspectives on the potential implications of eccDNA in life science.

Keywords: eccDNA; livestock; microDNA; molecular marker; tumor.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
A comprehensive classification of extrachromosomal circular DNAs (eccDNAs). We divide the general eccDNAs into two categories: narrow sense eccDNAs with length < 100 kb and ecDNAs common in tumors with size ranging from several 100 kb to several megabases. Small polydisperse circular DNA (spcDNA) was an obsolete concept to commonly characterize small eccDNAs with repetitive sequences. The length of extrachromosomal rDNA circles (ERCs) and t-circles is larger than that of spcDNA, which means that some ERCs and t-circles were not covered by spcDNA. The deletion of large genomic fragments could be circularized into episomes and subsequently polymerized into double-minutes.
Figure 2
Figure 2
Potential models for extrachromosomal circular DNA (eccDNA) generation: (A) formed by HR, (B) formed by NHEJ, (C) formed by DNA replication, and (D) formed by transcription. There are 11 kinds of potential mechanisms for eccDNA formation, and their detailed information can be found in the references listed in Table 1.
Figure 3
Figure 3
Methods for extrachromosomal circular DNA (eccDNA) identification. Microscopy and electrophoresis are used for eccDNA detection in total DNA after the enrichment of low-molecular-weight DNA [pictures were from Radloff et al. (8), Hahn (53), and Cohen et al. (54)]. Before rolling circle amplification or Tn5 treatment, eccDNAs with target size are enriched by CsCl-EB or a plasmid extraction kit. Split and discordant read pairs are crucial for eccDNA detection, which makes WGS and ATAC-seq data available as well. Various software packages have been developed to call eccDNA with sequencing data, including AmpliconArchitect, AmpliconReconstructor, CIRCexplorer2, Circle_finder, Circle-Map, and ECCsplorer (, –59). Comparisons have been made for some of these packages, and detailed information can be found in Prada-Luengo et al. (57).
Figure 4
Figure 4
Overview of our current understanding of extrachromosomal circular DNA (eccDNA) functions. High copy number and significant transcriptional activity of eccDNAs lead to the overexpression of the inhabiting genes. Additionally, eccDNAs could serve as mobile enhancers to trans-regulate chromosomal genes. eccDNAs have been associated with cancer prognosis, drug resistance of plants, and phenotypic variations of animals, implying their potential implications in life science. MicroDNA can be released from normal tissues. Establishing the associations of microDNA copy numbers with economic traits is an important direction for future exploration.
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