Extrachromosomal circular DNA: Current status and future prospects
- Department of Cardiology, The Second Affiliated Hospital of Soochow University, China
Figures
Figure 1
Models and pathways of extrachromosomal circular DNA (eccDNA) biogenesis.
(A) Chromothripsis model. Chromothripsis causes DNA fragmentation through catastrophic chromosomal breakage. A portion of the fragments is reassembled randomly through DNA repair mechanisms, including homologous recombination and nonhomologous end-joining (NHEJ). During the repair process, eccDNAs are generated and their chromosomal segments are lost. (B) Mild DNA damage. Only one arm of a chromosome generates DNA fragment via DNA double-strand breakage, from which the putative eccDNA fragment is produced and also results in a scarred chromosome. The ligation of these DNA fragment contributes to eccDNA formation. (C) Episome model. A drop in the replication bubble can cause episome formation when errors occur in DNA replication. Episome replication or recombination leads to the formation of eccDNA. (D) Breakage–fusion–bridge (BFB) cycle. The loss of telomeres in the chromosome is the earliest event of the BFB cycle. After being replicated, the telomere-free chromosomes can fuse and form a dicentric anaphase bridge. The above cycle was repeated to prolong the telomere-free bridge, ultimately falling off and circularizing into eccDNA. (E) Translocation–excision–deletion–amplification model. When gene translocation occurs, the fragments adjacent to translocation positions can be amplified or deleted. Then eccDNA forms after the circularization of DNA fragments. (F) Fork stalling and template switching mechanism. When a DNA lesion exists following DNA bidirectional replication, the lagging strand anneals to the template strand of the adjacent replication fork through the microhomology mechanism to continue DNA synthesis. The process abovementioned may be repeated many times until the lagging strand returns to the original template.
Figure 2
Extrachromosomal circular DNAs (eccDNAs) are associated with multiple human systems.
Several eccDNAs have been identified in multiple human systems such as nervous system, circulatory system, digestive system, immune system, musculoskeletal system, and genitourinary system.
Figure 3
Future research prospects for eccDNAs.
In basic research, the biogenesis of eccDNAs remains unclear, although numerous mechanistic models have been proposed. Further studies are required to investigate the regulatory mechanisms of eccDNAs in the occurrence and development of various diseases. Because of the limited tools currently available for analyzing eccDNAs, the development of new research methods is imperative. In clinical application, eccDNAs can be used as diagnostic and prognostic biomarkers because of their stable presence in human plasma. Moreover, eccDNAs are expected to serve as therapeutic targets for treating various diseases.
Tables
Table 1
Summary of extrachromosomal circular DNAs (eccDNAs) identified in various diseases.
| Name | Disease | Function | Reference |
|---|---|---|---|
| eccDNA (EGFR) | Glioblastoma | Endogenous enhancer elements | Shiras and Mondal, 2021 |
| ecDNA (ecEGFRx1, ecCCAT1, ecEGFR, and ecCCDC26) | Glioblastoma | Uneven segregation of ecDNA during mitosis | Yi et al., 2022 |
| eccDNA (PDGFRA, CDK4) | Radiation-induced high-grade glioma | eccDNA-mediated amplification of oncogenes | DeSisto et al., 2021 |
| eccDNA (TRPS1) | Breast cancer | TRPS1-driven genome deletions | Yang et al., 2021b |
| ecDNA (ecMYC) | Prostate cancer | Mobile transcriptional enhancers | Zhu et al., 2021 |
| ecDNA/eccDNA (cyclin-E1, ERBB2, CDK12, EGFR, MYC) | Gastric cardia adenocarcinoma | Focal amplifications of oncogene prognostic molecular markers | Zhao et al., 2021 |
| eccDNA (RAB3B) | Hypopharyngeal squamous cell carcinoma | Promote cisplatin resistance | Lin et al., 2022 |
| eccDNA (MYCN, CDK4, MDM2) | Neuroblastoma | Seismic amplification model | Rosswog et al., 2021 |
| eccDNA (entire genome) | Immune system | Trigger immune response | Wang et al., 2021 |
| TTNcircle | Musculoskeletal system | Function of transcription | Møller et al., 2018 |
| MI-related eccDNA (MIRECD) | Myocardial infarction (MI) | MI prognosis prediction and risk stratification | Not yet published |
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Extrachromosomal circular DNA: Current status and future prospects
eLife 11:e81412.
https://doi.org/10.7554/eLife.81412
