Double Minute Chromosomes Can Be Produced from Precursors Derived from a Chromosomal Deletion

Abstract

Recent experiments have shown that gene amplification can be mediated by submicroscopic, autonomously replicating, circular extrachromosomal molecules. We refer to those molecules as episomes (S. Carroll, P. Gaudray, M. L. DeRose, J. F. Emery, J. L. Meinkoth, E. Nakkim, M. Subler, D. D. Von Hoff, and G. M. Wahl, Mol. Cell. Biol. 7:1740-1750, 1987). The experiments reported in this paper explore the way episomes are formed and their fate in the cell over time. The data reveal that in our system the episomes are initially 250 kilobases, but gradually enlarge until they become double minute chromosomes. In addition, we show that episomes or double minute chromosomes can integrate into chromosomes. Our results also suggest that episomes can be produced by deletion of the corresponding sequences from the chromosome.

Extrachromosomal circular DNA in cancer: history, current knowledge, and methods

“…Episomes were isolated by denaturation and renaturation of DNA and visualized by gel electrophoresis. This work led to the development of an episome model in cancer genetics that states that episomes are formed by excision of linear DNA from chromosomes followed by circularization and amplification [4,[32][33][34]. ecDNA Next-generation sequencing (NGS)-based studies have in recent years allowed scientists to study the sequences of circular DNA from tumors in-depth.…”

“…Circularization could be mediated by the DNA repair pathways also involved in forming small eccDNA, as described previously. In some cases, ecDNA is suggested to arise by multistep processes, potentially from smaller precursors [32,40]. In others, large-scale DNA damage events have been proposed as the sources of ecDNA in cancer.…”

“…The gradual fusing of smaller eccDNA has been suggested as a formation mechanism for ecDNA. Later in its evolution, ecDNA has been demonstrated to integrate into chromosomes to create regions of gene amplifications known as homogeneously staining regions (HSRs) [32,59,60].…”

Circular DNA: How Circular DNA Assists Cancer Roll with Therapeutic Punches

“…All the events result in DNA sequence amplification at the telomeres that eventually loops out to form eccDNAs [59]. The fourth model is the episome model, which explains that excision of small circular DNA results in episome formation, which eventually results in recombination or over-replication, resulting in eccDNA formation [34,60]. It is well known that eccDNAs can lead to mutations, amplifications, translocations, deletions, etc.…”

Extrachromosomal Circular DNA (eccDNA): From Chaos to Function

“…It can be derived from everywhere in a genome with sizes ranging from hundreds of base pairs (bp) to several mega bases (Mb). According to the size and origin, eccDNAs can be categorized into mitochondria DNAs (mtDNAs), episomes, double minutes (DMs) (100kb∼3 Mb), telomeric circle (t-circles), small polydispersed circular DNA (spcDNA) (100bp∼10 kb), and microDNA (100–400 bp) ( Wang M et al, 2021 ).Some studies revealed that episomes can be polymerized into DMs in cancer cells suggesting the possibility that one type of eccDNA can be transformed to others by polymerization or fragmentation with subsequent recircularization ( Wahl et al, 1984 ; Carroll et al, 1988 ).…”