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Gene regulation on extrachromosomal DNA

Abstract

Oncogene amplification on extrachromosomal DNA (ecDNA) is prevalent in human cancer and is associated with poor outcomes. Clonal, megabase-sized circular ecDNAs in cancer are distinct from nonclonal, small sub-kilobase-sized DNAs that may arise during normal tissue homeostasis. ecDNAs enable profound changes in gene regulation beyond copy-number gains. An emerging principle of ecDNA regulation is the formation of ecDNA hubs: micrometer-sized nuclear structures of numerous copies of ecDNAs tethered by proteins in spatial proximity. ecDNA hubs enable cooperative and intermolecular sharing of DNA regulatory elements for potent and combinatorial gene activation. The 3D context of ecDNA shapes its gene expression potential, selection for clonal heterogeneity among ecDNAs, distribution through cell division, and reintegration into chromosomes. Technologies for studying gene regulation and structure of ecDNA are starting to answer long-held questions on the distinct rules that govern cancer genes beyond chromosomes.

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Fig. 1: Unique characteristics of ecDNA.
Fig. 2: ecDNA hubs drive oncogene expression and may shape cancer-cell evolution.
Fig. 3: Genetic and structural basis of the regulatory circuitry on ecDNA.
Fig. 4: Technologies used to reveal ecDNA gene regulation and structure.

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Acknowledgements

H.Y.C. is supported by US National Institutes of Health grant R35-CA209919 and is an Investigator of the Howard Hughes Medical Institute. P.S.M. is supported in part by grants U24CA264379 and R01 CA238249 from the US National Institutes of Health. H.Y.C. and P.S.M. are supported by Cancer Grand Challenges CGCSDF-2021\100007 with support from Cancer Research UK and the National Cancer Institute. K.L.H. is supported by a Stanford Graduate Fellowship.

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Hung, K.L., Mischel, P.S. & Chang, H.Y. Gene regulation on extrachromosomal DNA. Nat Struct Mol Biol 29, 736–744 (2022). https://doi.org/10.1038/s41594-022-00806-7

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