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Review
. 2022 Oct 26:20:6011-6022.
doi: 10.1016/j.csbj.2022.10.033. eCollection 2022.

Demystifying extrachromosomal DNA circles: Categories, biogenesis, and cancer therapeutics

Manrong Wu  1   2 , Kunal Rai  1   2
Affiliations
Review

Demystifying extrachromosomal DNA circles: Categories, biogenesis, and cancer therapeutics

Manrong Wu et al. Comput Struct Biotechnol J. .

Abstract

Since the advent of sequencing technologies in the 1990s, researchers have focused on the association between aberrations in chromosomal DNA and disease. However, not all forms of the DNA are linear and chromosomal. Extrachromosomal circular DNAs (eccDNAs) are double-stranded, closed-circled DNA constructs free from the chromosome that reside in the nuclei. Although widely overlooked, the eccDNAs have recently gained attention for their potential roles in physiological response, intratumoral heterogeneity and cancer therapeutics. In this review, we summarize the history, classifications, biogenesis, and highlight recent progresses on the emerging topic of eccDNAs and comment on their potential application as biomarkers in clinical settings.

Keywords: Biogenesis; Cancer therapeutics; Physiological response; eccDNA classification; eccDNAs.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
Models of ecDNA generation. A. Breakage-fusion-bridge cycle, B. Translocation-excision-deletion-amplification, C. Episome, and D. Chromothripsis.
Fig. 2
Fig. 2
Functional characteristics of eccDNAs. A. EccDNAs may function as innate immunostimulants that induce cytokine production. B. Cells carrying DMs at high concentration of methotrexate harbor altered dihydrofolate reductase enzyme, which has significant reduction of binding affinity for methotrexate, as measured by equilibrium dialysis. C. The complexity of eccDNA structure is exemplified by the hijacking of ectopic enhancer when the local enhancer is lost. A neoTAD could be formed by rearrangement during the process. D. EccDNAs could potentially mediate intercellular crosstalk. E. EccDNAs have been suggested by a few studies as biomarkers to progress disease surveillance, given that they are resistant to exonuclease and ribonuclease.
Fig. 3
Fig. 3
EccDNAs are mobile. A. DMs entrapped in micronuclei could be eliminated upon hydroxyurea treatment, suggesting opportunities to improve chemotherapeutic regimen. B. Clusters of eccDNAs could form a hub which promotes intermolecular interactions. BET protein such as BRD4 facilitates such interaction, which could be disrupted by the BET inhibitor JQ1. C. Proviral DNA circles could be used as substrates for host genome integration. Upon CRISPR/Cas9 ablation, DNA circles with LTR are accumulated. D. EccDNAs are associated with the telomeric regions of chromosome rosettes at the onset of anaphase, and the tethering process may mimic viral vector behavior. E. EccDNAs could function as mobile enhancers that globally amplify chromosomal transcription. On the contrary, synthetic eccDNAs not carrying enhancer regions do not increase genome-wide RNA expression. F. The loss of EGFRvIII carrying DMs are associated with EGFR TKI resistance, suggesting eccDNAs’ adaptation under environmental pressure.
Fig. 4
Fig. 4
EccDNA databases and their associated functional annotations.
See this image and copyright information in PMC

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References

    1. Navashin MS. Vol. 6. Cambridge University Press; Berkeley: 1930. Unbalanced somatic chromosomal variation in Crepis; pp. 95–106. (University of California publications in agricultural sciences).
    1. McClintock B. A correlation of ring-shaped chromosomes with variegation in Zea mays. PNAS. 1932;18(12):677–681. - PMC - PubMed
    1. Hotta Y, Bassel A. Molecular size and circularity of DNA in cells of mammals and higher plants. PNAS. 1965;53(2):356–362. - PMC - PubMed
    1. Stahl FW. Proc. Soc. de Chim. Phys, 11th Annual Reunion. 1962:194.
    1. Cox D, Yuncken C, Spriggs AI. Minute chromatin bodies in malignant tumours of childhood. Lancet. 1965;1(7402):55–58. - PubMed

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