UC Irvine scientists uncover ‘Nuclear RNA Degradation Code,’ shedding light on gene regulation and human disease

Irvine, Calif., Apr. 7, 2025 — Scientists at the University of California, Irvine have uncovered a sophisticated molecular mechanism that explains how cells identify and destroy specific RNA molecules, a finding that could have significant implications for understanding genetic diseases and gene regulation.

The study, recently published online in Molecular Cell, reveals a novel "nuclear RNA degradation code" (NRDC) that helps cells to eliminate improperly processed RNA transcripts. This mechanism involves a unique combination of molecular markers that signal certain RNA molecules for destruction.

Researchers found that two specific RNA sequence features — a 5′ splice site and a poly(A) junction — work together to trigger the degradation of RNA molecules. Individually, these features do not cause RNA destruction, but when they appear together, they act as a "degradation code" that targets RNAs for elimination by the cellular RNA degradation machinery.

“This revealed key information about quality control in cells,” said the study’s first author Lindsey Soles, PhD, working with Dr. Yongsheng Shi's laboratory in the Department of Microbiology & Molecular Genetics at UC Irvine's School of Medicine. “Before this, we had very little understanding of how cells were able to check whether RNAs are properly processed.”

The research has profound implications for understanding genetic diseases. The team identified 21 disease-associated genetic variations that could trigger aberrant RNA degradation. These "NRDC-activating" genetic variations were linked to a range of conditions, including a severe form of arthritis and depression.

The researchers demonstrated that this mechanism could explain how certain genetic mutations lead to disease by causing inappropriate RNA destruction. For two specific genes — Factor IX and p14 — they showed how a single genetic mutation could significantly reduce RNA levels through this degradation mechanism.

The study also suggests potential new therapeutic strategies. By blocking the RNA degradation process or the molecular interactions that trigger it, it might be possible to treat diseases caused by these genetic variations.

Beyond disease implications, this discovery provides new insights into how cells monitor and regulate gene expression. The researchers speculate that similar "degradation codes" might exist for other types of RNA molecules, opening up new avenues for research.

This study involved interdisciplinary collaboration, with contributions from researchers across UC Irvine, Shenzhen Bay Laboratory, Baylor College of Medicine and the University of Washington.

This work was supported by the National Institutes of Health under awards R35GM149294, R01CA297834, DP2GM149554; a Hewitt Foundation Postdoctoral Fellowship; and the Washington Research Foundation Postdoctoral Fellowship. Additional support was provided by UCI core facilities funded by P30CA062203, CA-62203, and NIH-S10OD032327-01.

About the UC Irvine School of Medicine
Each year, the UC Irvine School of Medicine educates more than 500 medical students and nearly 150 PhD and MS students. More than 750 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. For medical students, there are numerous concurrent dual degree programs, including an MD/MBA, MD/MPH, or an MD/MS degree through one of three mission-based programs: the Health Education to Advance Leaders in Integrative Medicine (HEAL-IM), the Program in Medical Education for Leadership Education to Advance Diversity-African, Black and Caribbean (PRIME LEAD-ABC), and the Program in Medical Education for the Latino Community (PRIME-LC). The UC Irvine School of Medicine is accredited by the Liaison Committee on Medical Accreditation and ranks among the top 50 nationwide for research. For more information, visit medschool.uci.edu.