A new study co-led by Pauline Pfuderer has revealed that extrachromosomal DNA (ecDNA) — rogue circular DNA fragments that fuel cancer growth and therapy resistance — replicate in a disorganised manner, leaving them vulnerable to agents that induce DNA replication stress.
The research, published this month in Nucleic Acids Research by scientists from the MRC Laboratory of Molecular Biology, University of Cambridge, ETH Zurich, and the Wellcome Sanger Institute, sheds light on how ecDNA behaves differently from normal chromosomes.
Unlike chromosomes, which follow an orderly program of DNA replication during the cell cycle, ecDNA was found to replicate asynchronously, with slowed replication forks and frequent stalling. When researchers induced replication stress using hydroxyurea, a common chemotherapy agent, ecDNA replication collapsed, ultimately causing cancer cells to lose these oncogene-loaded DNA circles.
The team introduced a new method called FINE (Fluorescence-activated Isolation of Native ecDNA), which allows intact ecDNA to be separated and studied without damaging its structure. Using advanced sequencing and replication-mapping technologies, they showed that replication origins on ecDNA are redistributed, replication is slower, and stress further accelerates their loss.
Because ecDNA is strongly linked to aggressive cancers, poor survival, and resistance to therapy, these insights may pave the way for new strategies to target ecDNA using agents that induce replication stress.
Read the paper here: https://doi.org/10.1093/nar/gkaf711