A research team from The Hong Kong University of Science and Technology (HKUST) has made a breakthrough discovery in understanding the molecular machinery of RNA silencing. The team uncovered how the human enzyme DICER achieves highly precise processing of microRNAs (miRNAs), advancing gene regulation research and offering new insights into the mechanisms underlying cancer, immune disorders, and genetic diseases.
This study, led by Prof. Tuan Anh NGUYEN, Associate Professor in the Division of Life Science at HKUST and jointly conducted by his PhD students Minh Khoa NGO and Cong Truc LE, has been published in the prestigious journal Nature under the title "DICER cleavage fidelity is governed by 5′-end binding pockets."
The message of human life is encoded in our genomic DNA through transcription of messenger RNAs which carries and executes the genetic instructions. RNA molecules, typically single-stranded and composed of ribonucleotides (A, U, G, and C), play essential cellular roles ranging from protein synthesis and gene regulation to serving as genetic material in certain viruses. Within this RNA-based regulatory landscape, the enzyme DICER functions as a highly precise "molecular scissors." It cleaves double-stranded RNA precursors into short regulatory RNAs that are subsequently incorporated into the RNA-induced silencing complex (RISC), enabling the cell to identify and suppress incorrect or unnecessary genetic messages-much like marking and deleting errors in a text.
For years, researchers have sought to understand how DICER achieves its extraordinary cleavage accuracy. Using state-of-the-art biochemical and structural biology techniques and high-resolution cryoelectron microscopy (cryo-EM), the HKUST research team visualized DICER-RNA interactions at an atomic level. The study's first author Minh Khoa Ngo explained, "CryoEM allowed us to observe how RNA substrates engage with DICER at an atomic detail. These structural snapshots vividly reveal the dynamic adjustments DICER makes when processing different RNA sequences, fundamentally reshaping our understanding of how this enzyme functions."
The team discovered that before cleavage occurs, DICER undergoes conformational adjustments that guide RNA substrates into the correct register. The enzyme then uses specific structural elements-particularly amino acids within 5′-end binding pockets-to align the RNA precisely before adopting the "cleavage ready" conformation.
Prof. Nguyen, the corresponding author, elaborated: "It is as if the scissors can 'read' exactly where the RNA should be cut at single nucleotide resolution, ensuring the integrity of the entire message. Our study uncovers not only the previously known U-favoured 5′-end binding pocket, but also a newly identified G-favoured 5′-end binding pocket. Together, these form a dual-pocket mechanism that determines cleavage positioning, providing an entirely new framework for understanding how DICER accommodates and processes diverse RNA substrates."
He further added: "The importance of this discovery extends beyond basic biology. By revealing how DICER integrates 5′-end identity, RNA motifs, and domain motions to maintain cleavage fidelity, our findings lay a mechanistic foundation for improving RNA-based therapeutics, optimizing gene silencing technologies, and uncovering the molecular origins of DICER-related genetic diseases."
