Origin of Extrachromosomal DNA and its Influence on Tumor Development / 中国生物化学与分子生物学报

ABSTRACT

Extrachromosomal DNA (ecDNA) is a class of circular DNA that is found off the chromosomes, either inside or outside the nucleus. ecDNA is abundant in cancer, and plays an important role during the tumor development. ecDNA contains multiple complete genes and regulatory elements that regulate transcription, including promoters and enhancers. It can replicate independently. However, the origin and mechanism of ecDNA is still unknown. Most scholars believe that DNA damage can elicit ecDNA production. The chromosomal fragments produced by DNA double-strand breaks are rearranged and circularized to form ecDNA via the non-homologous end-joining repair way. The chromatin on ecDNA is highly accessible and active. It works with oncogenes and co-amplify with enhancers to promote the transcription of oncogenes. Additionally, there are ultra-long-range chromatin contacts on ecDNA, which increases distant interaction. These features amplify the transcription of oncogenes and promote the development of tumors. Due to lack of centromeres, ecDNA has a non-equal segregation to daughter cells. Daughter cells, containing different copy numbers of ecDNA, can rapidly increase oncogene copy numbers, which drives the genome heterogeneity of the tumors. ecDNA-driven copy number regulation leads drug resistance and enables tumors to adapt quickly to the environment. Here we review the classification, origin of ecDNA and its role in tumorigenesis and development. We discuss the mechanisms of ecDNA promoting the transcription of oncogenes and leading to heterogeneity and drug resistance, aiming to provide new ideas on the diagnosis, treatment, and prognosis of tumors.