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What Is Extrachromosomal Circular DNA and What Does It Do?

It is known that DNA in the cell nucleus is packed in the form of linear chromosomes. For many years, researchers have observed smaller lengths of DNA alongside the chromosomes that are organized in circular forms. Some of these particles, which have been referred to as extrachromosomal circular DNA (eccDNAs) or microDNAs, are typically small (<1 kb), gene-sparse, and non-amplified. Total eccDNA abundance in cells can be up to a few hundred per cell. eccDNA molecules are also present in the circulation in cell-free form and offer the possibility to serve as blood-based biomarkers. In tumors, another type of extrachromosomal circular DNA can be detected, which appears to be exclusive to cancerous cells. Previously referred to as double minutes, but now referred to as extrachromosomal DNA (ecDNA) because they are usually not doublets, these ecDNA particles are often very large (mean size 1.3 Mb), highly amplified with many copies per cell, and contain many genes and regulatory regions, with a marked enrichment for oncogenes. Importantly, in cancer cells, ecDNAs seem to be more transcriptionally active than their chromosomal counterparts and have been suspected to confer growth and survival advantage to cancer cells. At present, the relationship between eccDNA in normal cells, and ecDNA in cancer, if there is one, is not understood. Being such an enigmatic form of genetic material, we posed questions about eccDNAs and ecDNAs to a panel of experts in the field who have studied facets of eccDNAs and ecDNAs, ranging from their biophysical properties, production mechanisms, physiological roles, roles in cancer biology, and diagnostic potential. What do eccDNAs do? What has been the biggest surprise to you about eccDNA so far?