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:	Preprint
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 and segregate stochastically during cell division yet persist over many generations. EcDNAs were first observed to hitchhike on mitotic chromosomes into daughter cell nuclei over 40 years ago with unknown mechanism. 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. We develop Retain-seq, a genome-scale assay that reveals thousands of human retention elements conferring generational persistence to heterologous episomes. Retention elements comprise a select set of CpG-rich gene promoters and act additively. Live-cell imaging and chromatin conformation capture show that retention elements physically interact with mitotic chromosomes at regions which are mitotically bookmarked by transcription factors and chromatin proteins, intermolecularly recapitulating 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, suggesting 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, revealing the principles of episome immortality intrinsic to the human genome.
Source:	bioRxiv
Publisher:	Cold Spring Harbor Laboratory Press
Article Number:	2025.10.10.681495
Date:	12 October 2025
Official Publication:	https://doi.org/10.1101/2025.10.10.681495
Related to:	URL URL Type https://www.ncbi.nlm.nih.gov/sra/?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/sra/?term=PRJNA1110283 External Dataset https://github.com/YosefLab/Cassiopeia Software

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