Fig. 1

Models of ecDNA formation. a Replication slippage model 1: ecDNA can be generated from replication slippage where DNA polymerase replicates DNA at wrong direction and creates a loop on the template strand. The loop is then excised and ligated into a circle, resulting in microdeletions at chromosomes. b Replication slippage model 2: ecDNA can be derived from replication slippage and recombination without deletion of original locus, leaving no chromosomal micro-gaps as they are filled by R-loop or homogenous recombination. This is more compatible when small regions of DNA containing one or a number of driver genes are selected. c Episome model: The ligation of DNA fragment pairs of inverted repeats in the replication bubble forms a single-strand circle when DNA replication is paused. d DSBs based model: in the process of DNA damage repair, DNA circle can be created by chromosomal rearrangements, which are mediated by the DNA damage repair mechanism non-homologous end-joining or microhomology-mediated end-joining. e Rolling circle model: Intrachromosomal recombination and "circularization" between tandem repeats produce circular molecules and shortened tandem sequences. f Translocation-deletion-amplification model: DNA segments derived from different chromosomes may form chimeric ecDNA sequences, which further invade and re-integrated into other chromosomes to generate novel DNA sequences