Unveiling the mysteries of extrachromosomal circular DNA: from generation to clinical relevance in human cancers and health

Abstract

Extrachromosomal circular DNAs (eccDNAs) are a type of circular DNAs originating from but independent of chromosomal DNAs. Nowadays, with the rapid development of sequencing and bioinformatics, the accuracy of eccDNAs detection has significantly improved. This advancement has consequently enhanced the feasibility of exploring the biological characteristics and functions of eccDNAs. This review elucidates the potential mechanisms of eccDNA generation, the existing methods for their detection and analysis, and their basic features. Furthermore, it focuses on the biological functions of eccDNAs in regulating gene expression under both physiological and pathological conditions. Additionally, the review summarizes the clinical implications of eccDNAs in human cancers and health.

Keywords: Cancer; Circle-Seq; Extrachromosomal Circular DNA; Generating mechanism; Human Health.

Fig. 1

The biological generating mechanisms of eccDNAs in vivo. A During the process of DNA replication and meiotic recombination, the excised DNA fragments can be circularized into eccDNAs through DNA damage repair mechanisms, including homologous recombination, NHEJ, MMEJ, mismatch repair, nucleotide excision repair and base excision repair. B Chromothripsis, episome model and BFB model were the major generating models of eccDNAs. C Apoptotic DNA fragments can be circularized into eccDNAs under the action of DNA ligase 3 after chromothripsis of apoptotic cells by DNase γ

Fig. 2

Flow diagram of the purification and detection of eccDNA by Circle-Seq

Fig. 3

The novel eccDNAs sequencing methods at the single-cell level

Fig. 4

The basic features of eccDNAs by Circle-Map

Fig. 5

The synthesis methods of eccDNAs in vitro

Fig. 6

The mechanisms of action for eccDNAs in the invasion of neoplasms

Fig. 7

Schematic diagram of the biological functions and differentially expressed genes of eccDNAs or ecDNAs in different cancers and non-neoplastic diseases