Researchers Uncover Structure of Important, Cancer-Linked Protein

Researchers from the University of California, Riverside (UCR), have recently discovered the structure of ZCCHC4, an RNA-modifying enzyme that influences cell proliferation and has been linked to cancer. In their work, they also identified the mechanism that controls how ZCCHC4 recognizes its substrate. This work was published on November 6 in the journal Nature Communications.

ZCCHC4 introduces an RNA modification known as N6-methyladenosine (m6A) into ribosomes (protein-manufacturing organelles made of RNA and proteins). Study leader Jikui Song, an associate professor of biochemistry at UC Riverside, explained that ZCCHC4 controls both protein synthesis and cell proliferation by bringing these m6A modifications into ribosomes. He also noted that ZCCHC4 is overexpressed in samples of hepatocellular carcinoma, the most commonly diagnosed form of primary liver cancer.

“This is the first time anyone has determined the crystal structure of ZCCHC4,” explained Song. “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.”

This m6A modification’s role in RNA metabolism and biology has brought a great deal of scientific attention to it in recent years. Despite this interest in the m6A modification, how it is dynamically programmed and distributed throughout the cells is not well understood.

“The structure of ZCCHC4 provides an understanding of how this enzyme is wired to specifically act on ’28S ribosomal RNA,'” Song said. He added that the ribosome is made of differently sized subunits and that 28S ribosomal RNA refers to the RNA component within the 28S subunit.

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

To reveal the structure of the cancer-associated ZCCHC4, Song and colleagues first created an enzymatically active ZCCHC4 fragment that was structurally rigid. They then crystallized this protein structure and performed an x-ray diffraction of the crystals. This data was analyzed, eventually yielding the structure of ZCCHC4.

Song’s lab is very familiar with this procedure, being that they identified the structure of an enzyme that is integral to DNA methylation using the same technique last year. Following this most recent discovery, Song and his team plan to explore how different DNA and RNA modifications in cells are made, being that these changes can play a strong role in patient health and diseases, including cancer.