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IBS Researchers See DROSHA for First Time

NEW YORK (GenomeWeb) - Researchers from the Institute of Basic Science (IBS) for RNA Research in South Korea have been able to get a clear image of the crystal structure of DROSHA, an RNase II enzyme from the Microprocessor complex, for the first time.

The researchers’ findings, published in the journal Cell, showed how DROSHA fits within the Microprocessor complex and how it functions, all of which helps researchers start to unravel how miRNA processes may come into play in cancer and genetic diseases.

The Microprocessor complex contains both DROSHA and the double-stranded RNA binding protein DGCR8. It measures primary miRNA then snips off its basal parts which results in precursor-miRNA. Further processing leads to mature miRNA and RNA-Induced Silencing Complex interacting with messenger RNA in the cytoplasm to repress translation, which stops the ribosome from making protein.

MiRNAs are important regulators in gene expression and they play crucial roles in almost all biological contexts including development, differentiation, inflammation, aging, and cancer. Gaining a better understanding of the mechanisms behind miRNA production may be important for understanding how gene expression goes wrong in cancer and genetic diseases.

While the processes within the Microprocessor complex have been studied, DROSHA's role is still poorly understood and researchers believe gaining insight into its function is crucial to better understanding miRNA biogenesis. Since DROSHA is easily aggregated during protein purification processes, researchers' attempts to gain insight by purifying the DROSHA protein have been hindered by technical difficulties.

To resolve these issues, the research team co-expressed 23 amino acids from DGCR8 that bind and cover the hydrophobic surface of DROSHA and help it maintain its structural integrity during purification. Without the hydrophobic interaction, the DROSHA proteins fold abnormally and aggregate, which renders them useless for close up imaging, IBS researcher Jae-Sung Woo said in a statement.

Since they were able to maintain the protein's structural integrity during purification, the researchers were able to perform x-ray crystallography to get the first clear image of its structure.

A close-up look at the protein's crystal structure confirmed the IBS team's previous findings that showed that DROSHA has two DGCR8-binding sites, giving a clear picture of how the Microprocessor is assembled.

The new study helped the researchers determine that the shape of DROSHA has unique physical characteristics, including a "bump" that could accommodate primary miRNA perfectly. They believe the bump may act as a measuring guide and indicate the 11-base pair distance for DROSHA to cleave.

Close analysis of DROSHA's structure also revealed an unexpected structural similarity to Dicer, another RNase III enzyme, offering an insight into the evolution of the RNase III family. Their research suggests that class II RNase III enzymes, such as DROSHA, may have evolved from class III RNase III enzymes, such as Dicer, in an early metazoan ancestor. This could have led to the emergence of animal miRNAs. 

Achieving this imaging breakthrough opens the door for a better understanding and exciting new applications in cell reproduction, the researchers said. They believe that building on this knowledge is the basis for devising new ways to regulate and control gene expression, which has a range of applications including building new antifungals and stopping tumor growth.

"In the future, we are planning to solve the structure of pri-miRNA bound Microprocessor complex," added IBS researcher Sung Chul Kwon in a statement.