Molecular mechanisms of extrachromosomal circular DNA formation

Recent research reveals that eukaryotic genomes form circular DNA from all parts of their genome, some large enough to carry whole genes. In organisms like yeast and in human cancers, it is often observed that extrachromosomal circular DNA (eccDNA) benefits the individual cell by providing resources for rapid cellular growth. However, our comprehension of eccDNA remains incomplete, primarily due to their transient nature. Early studies suggest they arise when DNA breaks and is subsequently repaired incorrectly. In this review, we provide an overview of the evidence for molecular mechanisms that lead to eccDNA formation in human cancers and yeast, focusing on nonhomologous end joining, alternative end joining, and homologous recombination repair pathways. Furthermore, we present hypotheses in the form of molecular eccDNA formation models and consider cellular conditions which may affect eccDNA generation. Finally, we discuss the framework for future experimental evidence.