Genetic elements promote retention of extrachromosomal DNA in cancer cells

Sankar, Venkat; Hung, King L.; Gnanasekar, Aditi; Wong, Ivy Tsz-Lo; Shi, Quanming; Kraft, Katerina; Jones, Matthew G.; He, Britney Jiayu; Yan, Xiaowei; Belk, Julia A.; Liu, Kevin J.; Agarwal, Sangya; Wang, Sean K.; Henssen, Anton G.; Mischel, Paul S.; Chang, Howard Y.

Genetic elements promote retention of extrachromosomal DNA in cancer cells

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Item Type:	Article
Title:	Genetic elements promote retention of extrachromosomal DNA in cancer cells
Creators Name:	Sankar, Venkat, Hung, King L., Gnanasekar, Aditi, Wong, Ivy Tsz-Lo, Shi, Quanming, Kraft, Katerina, Jones, Matthew G., He, Britney Jiayu, Yan, Xiaowei, Belk, Julia A., Liu, Kevin J., Agarwal, Sangya, Wang, Sean K., Henssen, Anton G., Mischel, Paul S. and Chang, Howard Y.
Abstract:	Extrachromosomal DNA (ecDNA) is a prevalent and devastating form of oncogene amplification in cancer. Circular megabase-sized ecDNAs lack centromeres, stochastically segregate during cell division and persist over many generations. It has been more than 40 years since ecDNAs were first observed to hitchhike on mitotic chromosomes into daughter cell nuclei, but the mechanism underlying this process remains unclear. Here we identify a family of human genomic elements, termed retention elements, that tether episomes to mitotic chromosomes to increase ecDNA transmission to daughter cells. Using Retain-seq, a genome-scale assay that we developed, we reveal thousands of human retention elements that confer generational persistence to heterologous episomes. Retention elements comprise a select set of CpG-rich gene promoters and act additively. Live-cell imaging and chromosome conformation capture show that retention elements physically interact with mitotic chromosomes at regions that are mitotically bookmarked by transcription factors and chromatin proteins. This activity intermolecularly recapitulates promoter–enhancer interactions. Multiple retention elements are co-amplified with oncogenes on individual ecDNAs in human cancers and shape their sizes and structures. CpG-rich retention elements are focally hypomethylated. Targeted cytosine methylation abrogates retention activity and leads to ecDNA loss, which suggests that methylation-sensitive interactions modulate episomal DNA retention. These results highlight the DNA elements and regulatory logic of mitotic ecDNA retention. Amplifications of retention elements promote the maintenance of oncogenic ecDNA across generations of cancer cells, and reveal the principles of episome immortality intrinsic to the human genome.
Source:	Nature
ISSN:	0028-0836
Publisher:	Nature Publishing Group
Date:	19 November 2025
Official Publication:	https://doi.org/10.1038/s41586-025-09764-8
PubMed:	View item in PubMed
Related to:	URL URL Type https://www.ncbi.nlm.nih.gov/bioproject/?term=PRJNA1333946 External Dataset https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE46189 External Dataset https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSM7956899 External Dataset https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSM7956900 External Dataset https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSM8523315 External Dataset https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSM8523316 External Dataset https://www.ncbi.nlm.nih.gov/bioproject/?term=PRJNA1110283 External Dataset https://doi.org/10.6084/m9.figshare.30239047.v1 External Dataset https://github.com/YosefLab/Cassiopeia Software

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