(from left) Yiping Xie, B.S., Yoon Jung Kim, Ph.D., and Sihan Wu, Ph.D., stand in front of advanced genomic sequencing equipiment in the CRI Sequencing Core.
Targeting transcription machinery could disturb ecDNA maintenance, reduce oncogenicity
Dallas – June 24, 2026 – Extrachromosomal DNA (ecDNA) — circular, fractured chromosomal DNA found in the nucleus of many cancer cells — anchors to H3K27ac-marked active regions on chromosomes to survive normal mitotic cell division and persist into the next generation of daughter cells, according to research from Children’s Medical Center Research Institute at UT Southwestern (CRI), published today in Nature Cell Biology.
This anchoring is driven by key components of the cell’s inherent transcriptional machinery, which include bromodomain proteins, the Mediator complex, and RNA Polymerase II (Pol II). Together, these proteins act as a bridge, allowing ecDNA to hitchhike onto chromosomes and fuel cancer cell growth in the next generation.
The study led by Sihan Wu, Ph.D., Assistant Professor at CRI and of Pediatrics, and Yoon Jung Kim, Ph.D., Assistant Professor of Research in CRI and of Pediatrics, shows transcription machinery bridges the interaction between ecDNAs and chromosomes before cancer cell division begins. Once cells start to divide, the processes of chromosome condensation and transcriptional silencing remove the Mediator complex. However, bromodomain proteins and inactive Pol II remain and maintain ecDNA anchorage to accessible H3K27ac regions.
These findings solve a long-standing biological puzzle. Since ecDNAs lack functional centromeres — the essential structures that cells use to partition chromosomes during cell division — researchers have struggled to explain how ecDNAs avoid being ejected into the cytosol and degraded, Dr. Wu said.
First author Yipeng Xie, B.S., a graduate student researcher in the Wu Lab from the UT Southwestern Genetics, Development and Disease graduate program, led the experimental efforts. Using advanced genomic sequencing, the team revealed that p-Pol II S2/5 — the active form of Pol II, which is essential to uncoil DNA for transcription — was largely absent from ecDNAs during mitosis.
In addition, researchers found MED14 — an essential structural component of the Mediator complex required for signaling before mitosis — was undetectable on ecDNAs during mitosis. Instead, inactive Pol II remained on ecDNAs, which tethered ecDNAs to chromosomes during cell division.
Unlike normal chromosomes, ecDNA molecules aren’t equally split into daughter cells. Instead, they are distributed randomly when a cancer cell divides.
“This random distribution creates a highly diverse mix of cancer cells, with some inheriting massive numbers of cancer-driving genes,” Dr. Wu said. “This cellular diversity is exactly what makes these tumors so aggressive and incredibly difficult to treat.”
When researchers inhibited components of the transcription machinery, ecDNAs failed to hitch a ride and distribute correctly. Instead, cancer-driving ecDNAs were cast out from the nucleus into the cytosol and gradually destroyed. The study showed cells lost oncogene expression, as well as lost their resistance to certain cancer therapies.
“This finding opens a new avenue for treating ecDNA-driven cancer by targeting ecDNA inheritance,” Dr. Wu said. “Our future studies will aim to determine if we can eliminate these tumors by blocking the specific pathways ecDNAs rely on to pass themselves down during cell division.”
Dr. Wu is a Cancer Prevention Research Institute of Texas (CPRIT) Scholar in Cancer Research and member of eDyNAamiC, a group of cancer researchers supported by the Cancer Grand Challenges initiative.
This research was supported by CPRIT, the American Cancer Society, Gilead’s Research Scholars Program in Solid Tumors, the Cancer Challenges partnership through Cancer Research UK, and the National Cancer Institute.
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About CRI
Children’s Medical Center Research Institute at UT Southwestern (CRI) is a joint venture of UT Southwestern Medical Center and Children’s Medical Center Dallas. CRI’s mission is to perform transformative biomedical research to better understand the biological basis of disease. Located in Dallas, Texas, CRI is home to interdisciplinary groups of scientists and physicians pursuing research at the interface of regenerative medicine, cancer biology, and metabolism – relentless discovery toward the treatments of tomorrow.
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