New Screening Approach Advances Understanding of Defective Alternative RNA Processing

Most human genes produce proteins through a process called alternative RNA processing. How the body regulates this process isn’t well understood, but defective alternative RNA processing has been linked to a variety of diseases, including cancer, with processing dysregulation promoting tumor growth and drug resistance.

To better understand what is going on behind the scenes, UC Irvine researchers teamed up with colleagues from UC San Diego to analyze alternative polyadenylation (APA), a fundamental step in the gene expression process. The goal was to explore options for addressing APA dysregulation.

Together, the researchers carried out the largest screening of RNA-binding proteins, looking at 879 proteins.

“Our screen and AI-based analyses are not only among the most comprehensive analyses of regulators of alternative RNA processing,” says Yongsheng Shi, PhD, a professor of microbiology and molecular genetics at UC Irvine. “They also provide new links between alternative RNA processing and diseases, including cancer.”

The study identified novel regulators of alternative RNA processing, including GRB2, the growth factor receptor-bound protein whose mutations have been linked to cancer.

Shi worked with Yoseop Yoon, PhD, a postdoctoral scientist in the Shi Lab, and Gene Yeo, a professor of cellular and molecular medicine at UC San Diego, among others, on the study. Their findings appear in a paper published in Molecular Cell: “Large-scale tethered screen of RNA-binding proteins reveals novel regulators of poly(A) site selection.”

“In future studies,” says Shi, “we will characterize the novel factors that we found in our current study to better understand how they regulate alternative RNA processing and contribute to disease.”

— Shani Murray