Abstract
With advances in sequencing technologies and molecular tools, extrachromosomal circular DNA (eccDNA), once considered a mere by-product of genomic instability, is now recognized as playing important roles in genome plasticity, gene regulation, and cancer. In this review, we provide a comprehensive overview of eccDNA from its historical origins to the current state of the field. We distinguish between small eccDNAs and large eccDNAs. Small eccDNAs are usually too small to encode full genes and arise through DNA repair and replication-associated processes, while large eccDNAs carry full genes that drive oncogene amplification and tumor evolution. We summarize the current understanding of their mechanisms of biogenesis, functions, and emerging diagnostic and therapeutic applications. In addition, we discuss the broad spectrum of diseases associated with eccDNA, including cancer and aging-related diseases, as well as recent advances in engineering platforms and computational tools that are transforming our ability to study eccDNA structure and biology.