The first map of replication fork movement across extrachromosomal DNA
- Admin
- Aug 12
- 1 min read
Together with Julian Sale's Lab at the MRC Laboratory of Molecular Biology, we published a paper entitled "ecDNA replication is disorganized and vulnerable to replication stress" that uses DNAscent to show how replication forks move across extrachromosomal DNA (ecDNA). This work was led by Julian's PhD student Jedrzej Jaworski (now a medical student at the University of Oxford) and our PhD student Pauline Pfuderer.
ecDNA is DNA found outside of chromosomes and these fragments often harbour oncogenes that drive tumour growth and evolution. Together, we showed that ecDNA in the COLO 320DM colorectal cancer cell line replicates asynchronously throughout S-phase and displays different patterns of replication origin activation compared to the same fragment of DNA in a chromosome. Moreover, we found that DNA replication forks move slowly across ecDNA and were more prone to stalling. When we treated ecDNA-containing cells with hydroxyurea, forks moving on ecDNA slowed further and displayed further changes in origin activation compared to the untreated case. Ultimately, these findings show that agents that affect the movement and fidelity of replication forks are a viable option for targeting ecDNA in cancer cells.
We are very grateful to the superb staff at the Cambridge Service for Data-Driven Discovery, without whom we would not have been able to manage the high volume of data that made this project possible. We are also grateful to Cancer Research UK for funding Pauline's work, as well as the whole team for a really fantastic collaboration.
Team
