About the Project

A major focus of the lab is understanding the links between replication and mutagenesis (1‑4). Extrachromosomal DNA (ecDNA) circles are present in a substantial proportion of cancers and frequently harbour oncogenes that drive tumour proliferation (5). The mechanisms governing their replication, and the extent to which this mirrors replication of the corresponding chromosomal loci, remain poorly understood. In addition to self-maintenance, ecDNAs can reintegrate into the host genome, often…

forming tandem arrays known as homogenously staining regions (HSRs). Such reintegration events have the potential to disrupt chromosome architecture, yet the molecular processes underlying this transition remain unclear.

Our recent work shows that ecDNA replication is disorganised both in the location of DNA synthesis initiation and in its timing during S phase (6). Replication on ecDNA also appears more fragile, with increased fork stalling. How these stalled forks are rescued, and whether the underlying mechanisms are linked to ecDNA reintegration, is unknown.

This project will employ established ecDNA-containing cancer cell line models alongside synthetic ecDNA constructs. Using CRISPR-based genetic perturbations combined with high-resolution replication mapping, we will dissect the molecular mechanisms that sustain ecDNA replication and examine how these processes interface with pathways leading to reintegration. These questions have relevance beyond cancer biology: the Synthetic Human Genome (SynHG) project proposes to build synthetic chromosomes in part via episomal intermediates that must ultimately integrate into the host genome (7). Insights into how natural ecDNA circles achieve stable reintegration will help define the mechanisms and sequence features governing efficient, high-fidelity integration of engineered episomes, informing next-generation genome-writing strategies. Our ultimate aim is to clarify the balance between ecDNA maintenance and reintegration, understand how this balance shapes genome architecture and tumour evolution, and apply this knowledge to harnessing episomal integration for synthetic genomics.

References

Murat,P., Guilbaud,G. and Sale,J.E. (2020) DNA polymerase stalling at structured DNA constrains the expansion of short tandem repeats. Genome Biol 21, 209.
Guilbaud,G., Murat,P., Wilkes,H.S., Lerner,L.K., Sale,J.E. and Krude,T. (2022) Determination of human DNA replication origin position and efficiency reveals principles of initiation zone organisation. Nucleic Acids Res 50, 7436-7450.
Murat,P., Perez,C., Crisp,A., van Eijk,P., Reed,S.H., Guilbaud,G. and Sale,J.E. (2022) DNA replication initiation shapes the mutational landscape and expression of the human genome. Sci Adv 8, eadd3686.
Murat,P., Guilbaud,G. and Sale,J.E. (2024) DNA replication initiation drives focal mutagenesis and rearrangements in human cancers. Nat Commun 15, 10850.
Yan,X., Mischel,P. and Chang,H. (2024) Extrachromosomal DNA in cancer. Nat Rev Cancer 24, 261-273.
Jaworski,J.J., Pfuderer,P.L., Czyz,P., Petris,G., Boemo,M.A. and Sale,J.E. (2025) ecDNA replication is disorganized and vulnerable to replication stress. Nucleic Acids Res 53, gkaf711.
Petris,G., Grazioli,S., van Bijsterveldt,L., Murat,P., Liu,K.C., Birnbaum,J., Sale,J.E. and Chin,J.W. (2025) High-fidelity human chromosome transfer and elimination. Science 390, 1038-1043.

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The life cycle of ecDNA

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Grants to USA, Canada, and International Senior Sleep Researchers to Help Apply for Federal Funds

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Fellowship to a USA, Canada, or International PhD or MD for Cancer Research Studies

Grants to USA, Canada, and International Scientists for Security Research

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The life cycle of ecDNA

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Cambridge, United Kingdom

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Grants to USA, Canada, and International Senior Sleep Researchers to Help Apply for Federal Funds

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