Gene Amplification and the Extrachromosomal Circular DNA.

Noriaki Shimizu

doi:10.3390/genes12101533

Abstract

Oncogene amplification is closely linked to the pathogenesis of a broad spectrum of human malignant tumors. The amplified genes localize either to the extrachromosomal circular DNA, which has been referred to as cytogenetically visible double minutes (DMs), or submicroscopic episome, or to the chromosomal homogeneously staining region (HSR). The extrachromosomal circle from a chromosome arm can initiate gene amplification, resulting in the formation of DMs or HSR, if it had a sequence element required for replication initiation (the replication initiation region/matrix attachment region; the IR/MAR), under a genetic background that permits gene amplification. In this article, the nature, intracellular behavior, generation, and contribution to cancer genome plasticity of such extrachromosomal circles are summarized and discussed by reviewing recent articles on these topics. Such studies are critical in the understanding and treating human cancer, and also for the production of recombinant proteins such as biopharmaceuticals by increasing the recombinant genes in the cells.

Highlights

Graduate School of Integrated Sciences for Life, Hiroshima University, 1-7-1 Kagamiyama, Abstract: Oncogene amplification is closely linked to the pathogenesis of a broad spectrum of human malignant tumors
It is important to note that gene expression from the same amplicon sequence is higher in the extrachromosomal context than in the chromosomal context [15] because the chromatin of extrachromosomal DNA is more favorable for gene expression [8,16]
If such a circle is integrated into the chromosome arm, it induces clear matrix attachment region (MAR/SAR), both of which are required for repthe breakage-fusion-bridge cycle (BFB) and generates chromosomal homogeneously staining region (HSR)

Summary

Gene Amplification and the Extrachromosomal Circles in Human Cancer

The amplification of oncogenes or drug-resistant genes plays a pivotal role in human cell malignant transformation by conferring growth advantage to the cells through the overproduction of the amplified gene product. The circles in normal cells [11,12] were smaller in size (less than 1 kbp) than those in cancer cells (1–2 Mbp) [13] The former is referred to as extrachromosomal closed circular DNA (eccDNA), and the latter are referred to as extrachromosomal DNA (ecDNA). It is important to note that gene expression from the same amplicon sequence is higher in the extrachromosomal context than in the chromosomal context [15] because the chromatin of extrachromosomal DNA is more favorable for gene expression [8,16]. The higher gene expression may reflect the amplicon were replicated at the end of the S phase [4]. The higher gene expression circular nature that poses a topological constraint that favors DNA helix unwinding [8]. Gene expression is favored [17]

Intra-Cellular

Mechanism

From Chromosome Arm to Gene Amplification

Applications of the Extrachromosomal Element-Mediated Gene Amplification

Future Task