UC Irvine Researchers Discover Cellular ‘Tug-of-War’ That Shapes How Our Genes Are Expressed — With Potential Implications for Cancer Drug Safety

Irvine, Calif., May 15, 2026 — Scientists at the University of California, Irvine have uncovered a fundamental competition occurring inside our cells that determines how genetic instructions are read and carried out. The findings, which reveal a molecular "tug-of-war" between two essential processes in gene expression, also raise important safety considerations for certain cancer treatments currently in development.

The study, published online today in Genes & Development, demonstrates that two crucial steps in processing genetic messages — splicing and 3′ end processing — actively compete with each other to shape what RNA molecules are generated.

When cells read genetic instructions from DNA, they first create a rough draft called pre-mRNA. The pre-mRNA undergoes several processing steps before becoming a mature mRNA, which can be used to make proteins. Two of these processing steps include splicing, which removes non-coding segments (introns) from this draft, and 3′ end processing, which adds a protective tail that stabilizes the message.

"We found that these two processes aren't just working independently, they're actually competing for control of the same genetic messages," said Lindsey Soles, PhD, the study's first author, now a postdoctoral scientist at Johns Hopkins University after graduating from UC Irvine last spring. "When one process is disrupted, the other takes over, fundamentally changing which proteins a cell can make."

Using six different methods to inhibit splicing, the research team discovered that blocking this process activates thousands of intronic polyadenylation (IPA) sites — locations within genes where 3′ end processing can occur prematurely. This often results in shortened, non-functional genetic messages. Conversely, blocking 3′ end processing improved splicing efficiency, consistent with the author’s proposed competition model.

The findings carry significant implications for ongoing efforts to develop cancer treatments that target the splicing machinery. Several small-molecule inhibitors of splicing, including Pladienolide B and its derivatives, are being explored as potential cancer therapeutics.

However, the UC Irvine team's research reveals a potential concern: when splicing is inhibited, IPA becomes activated in many genes, including tumor suppressor genes that normally protect cells from becoming cancerous.

"Our study suggests that caution must be taken when using general splicing inhibitors to treat diseases," said Yongsheng Shi, PhD, Professor & Chancellor's Fellow in the Department of Microbiology & Molecular Genetics, who is the study's corresponding author. "These drugs may inadvertently inactivate genes that protect against cancer, potentially representing a serious risk."

Understanding how cells regulate gene expression is essential for the development of safe and effective treatments for diseases ranging from cancer to genetic disorders. This research provides a new framework for understanding how gene expression is shaped by competing cellular processes.

This work was supported by the National Institutes of Health under awards R35GM149294, R01AI170840-03S1 and a Hewitt Foundation Postdoctoral Fellowship. Additional support was provided by UCI core facilities funded by P30CA062203, CA-62203, and NIH-S10OD032327-01.

For full details, refer to the The competition between splicing and 3′ processing shapes the human transcriptome” study in Genes & Development.

About the UC Irvine School of Medicine: Each year, the UC Irvine School of Medicine educates more than 500 medical students and over 180 PhD and MS students. Nearly 900 residents and fellows are trained at the UCI Medical Center and affiliated institutions. The School of Medicine offers multiple MD, PhD and MS degrees, and students are encouraged to pursue an expansive range of interests and options. The UC Irvine School of Medicine is accredited by the Liaison Committee on Medical Education and ranks among the top 50 nationwide for research. For more information, visit medschool.uci.edu.