Article Impact Level: HIGH Data Quality: STRONG Summary of Nature https://doi.org/10.1038/s41586-025-09764-8 Dr. Venkat Sankar et al.
Points
- The study utilized a novel screening method called Retain-seq to identify over fourteen thousand genomic sequences that enable acentromeric DNA to persist through cell division.
- These retention elements are primarily CpG-rich gene promoters that facilitate the tethering of extrachromosomal DNA to mitotic chromosomes during the segregation process.
- Researchers discovered that these elements interact physically with regions known as mitotic bookmarks which usually preserve cellular memory and gene expression patterns in daughter cells.
- Experimental data indicated that targeted methylation of these specific cytosine sequences successfully disrupted retention activity and resulted in the subsequent loss of the cancer-driving DNA.
- This mechanism explains how extrachromosomal DNA hitchhikes on chromosomes to ensure the inheritance of amplified oncogenes associated with metastasis and poor survival rates in patients.
Summary
This study investigated the mechanism by which extrachromosomal DNA (ecDNA) segregates to daughter cells despite lacking centromeres, a phenomenon observed in 17.1% of tumors. ecDNA amplification drives oncogene overexpression and is associated with metastasis and reduced survival. To elucidate how these acentromeric molecules persist, researchers developed Retain-seq, a genome-scale screening assay involving hybrid bacterial-human DNA constructs, to identify specific genomic sequences capable of mediating inheritance during mitosis.
The analysis identified over 14,000 “retention elements” that facilitate the tethering of episomes to mitotic chromosomes. These elements primarily consist of CpG-rich gene promoters that are focally hypomethylated. Validation studies focused on six specific elements similar to those found in colorectal and brain cancers. The mechanism relies on physical interactions between these retention elements and “mitotic bookmarks”—regions where transcription factors and chromatin proteins remain bound during cell division to preserve cellular memory.
Targeted cytosine methylation of these sequences was shown to abrogate retention activity, leading to ecDNA loss. This suggests that methylation-sensitive interactions are critical for episomal persistence. By mimicking promoter-enhancer interactions, these elements allow ecDNAs to “hitchhike” on chromosomes. These findings define the regulatory logic of ecDNA inheritance, offering potential therapeutic targets to disrupt the maintenance of oncogenic amplifications in cancer cells.
Link to the article: https://www.nature.com/articles/s41586-025-09764-8
References
Sankar, V., Hung, K. L., Gnanasekar, A., Wong, I. T.-L., Shi, Q., Kraft, K., Jones, M. G., He, B. J., Yan, X., Belk, J. A., Liu, K. J., Agarwal, S., Wang, S. K., Henssen, A. G., Mischel, P. S., & Chang, H. Y. (2025). Genetic elements promote retention of extrachromosomal DNA in cancer cells. Nature, 1–9. https://doi.org/10.1038/s41586-025-09764-8
