Structure of a novel enzyme linked to cell growth and cancer cracked

Structure of a novel enzyme linked to cell growth and cancer cracked
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A new UC Riverside-led study could lead to the development of drugs that target liver and other cancers.

RNA, or ribonucleic acid, is present in the cells of all living beings and required to synthesise proteins. A research team at the University of California, Riverside, has discovered the structure of a novel RNA-modifying enzyme, ZCCHC4, which is linked to cell growth and cancer, and have identified the mechanism that controls how this enzyme recognises its substrate.

ZCCHC4 influences cell proliferation and has been linked to cancers. It uniquely introduces one kind of RNA modification, N6-methyladenosine (m6A), into ribosomes, which are cell organelles made up of RNA molecules and protein.

The study, published in Nature Communications, explains how protein machineries in cells are regulated to target RNA molecules for m6A modification.

Cracking the crystal structure

Jikui Song, an associate professor of biochemistry at UC Riverside who led the study, explained ZCCHC4 controls protein synthesis and cell proliferation by introducing an m6A modification into ribosomes.

ZCCHC4, which is linked to cell growth and cancer, he added, is overexpressed in tumours associated with hepatocellular carcinoma – the most common type of primary liver cancer. Song said: “This is the first time anyone has determined the crystal structure of ZCCHC4.

“Our discovery can be used for structure-based drug design against cancers and lead to a better understanding of how m6A, a modification associated with numerous biological processes, is installed on ribosomal RNA.”

The m6A modification has received enormous attention in recent years due to the important role it plays in RNA metabolism and biology. How this modification is dynamically programmed and distributed in cells, however, remains poorly understood.

Song noted that a ribosome is assembled with differently sized subunits. 28S ribosomal RNA refers to the RNA component in the 28S ribosomal subunit. He said: “The structure of ZCCHC4 provides an understanding of how this enzyme is wired to specifically act on ’28S ribosomal RNA.

“We now understand that this enzyme is controlled by an ‘autoinhibitory’ mechanism that has been observed in many other cellular processes.”

To crack the structure of ZCCHC4, Song’s team first produced an enzymatically active and structurally rigid ZCCHC4 fragment. The researchers then coaxed this protein to crystallise. Finally, they diffracted the crystals using X-rays and analysed the data, which led to the eventual discovery of ZCCHC4’s structure.

Next, the research team will continue to explore how various DNA and RNA modifications in cells are created, which has strong implications in health and diseases.

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