Science & Technology

Why the eraser enzyme doesn’t work and leads to cancer

Biochemists are studying cases where enzymes in our cells fail and malfunction in human illness.

Researchers at the University of Delaware have awarded a NIH grant to study why eraser enzymes fail and lead to cancer.

Jeff Mugridge, a biochemist at the University of Delaware, explains how so-called mRNA eraser enzymes work inside cells, why those erasers can sometimes malfunction and cause cancer, and science is possible for this problem. I’m trying to figure out how to pave the way for a solution.

Revolving nuclei acid ((((RNA) Is a single-stranded molecule copied from. DNA In our body. Messenger RNA (mRNA) molecules have instructional codes that tell cells everything they need to survive, such as when, where, and how to make proteins and enzymes.

One of the many ways our cells in the body control mRNA molecules is to decorate them with various chemical groups that subtly or dramatically change the way messages are transmitted.

Mugridge, an assistant professor of chemistry and biochemistry, was recently awarded $ 1,956,466 by the National Institutes of Health (NIH) to act like a scavenger and remove important chemical groups called methyl groups in mRNA molecules. I studied a specific enzyme.

In difficult-to-treat cancers such as glioblastoma, these methyl eraser enzymes can be overexpressed in cancer cells. In other words, there are too many eraser enzymes that work at one time. This can lead to a lack of important information in the mRNA molecule, which can alter the message delivered by the mRNA molecule in a way that leads to cancer progression and tumor growth.

Jeff Magridge Examining Eraser Enzymes

Jeff Magridge, an assistant professor at the University of Delaware, is studying scavenging enzymes that can remove important chemical groups from mRNA, a molecule in the body that carries instructions and codes to function in cells. This study may inform you of treatment options for various human illnesses where these eraser enzymes malfunction.Credit: Photo by Evan Krape

Little is known about how these eraser enzymes determine which methyl groups they remove or retain, how often they eliminate the methyl groups in healthy cells, or why they malfunction in some human illnesses.

Make fun of the basic details

Mugridge, along with two PhD students working in his lab, is specifically investigating a class of eraser enzymes called RNA demethylase. Demethylase removes the methyl groups of RNA that play an important role in gene expression and the progression of cancers such as glioblastoma and acute myeloid leukemia.

RNA methylation is a biochemical process that acts like a switch and can turn certain activities inside the cell on or off. In particular, it is known to be important for producing properly shaped RNA molecules, synthesizing proteins, and determining the lifespan of RNA molecules in cells. Methyl modification of mRNA also affects cell fate determination and the way embryonic stem cells differentiate during development.

Scientists have recently identified several RNA-methyl modified erasers. This can cause these methyl groups to be written and erased from the mRNA transcript. However, it is not well known which specific methyl groups these eraser enzymes recognize and remove from the thousands of methyl groups found in RNA, and how often they do this.

Does it always happen or is it a rare event? Does it only occur with diseases or specific cell types? These are some of the questions Magridge and his team will answer. The researchers will also investigate how other cofactors, such as proteins and vitamin C, regulate intracellular demethylase activity.

“In the long run, a high-resolution understanding of how these demethylase enzymes work can help us begin to understand how each eraser is associated with various human illnesses and disease progression. You can, “says Mugridge. “This provides better information about which of these enzymes are targeted for inhibition, for example, how to slow the progression of cancer.”

For example, glioblastoma overexpresses an eraser enzyme known as FTO. That is, glioblastoma cells produce far more enzymes than normal cells. This leads to a large amount of methyl scavenging activity on the RNA of those cancer cells, which appears to be important for cancer progression. Studies show that drug inhibition of the FTO slows the progression of glioblastoma cancer. However, therapies that can selectively and effectively target RNA demethylase enzymes to treat cancer have avoided scientists.

If Mugridge and his team can understand the molecular details of how these demethylase enzymes function and how cells regulate their function, which methyl groups are eliminated from RNA. You can find a way to operate and pave the way for a cure that will help you fix the misleading eraser. Illness enzyme.

“Understanding how RNA molecules bind, where they bind to the surface of a protein, and how they interact with a particular molecule. amino acid Since it constitutes a protein, we may be able to fill in the missing parts of the puzzle and then develop tools to monitor or influence this erasing activity in the cell, “he said.

Look for clues to the details

At the Brown Institute, Magridge and his students produce proteins in bacterial cells to purify and isolate specific RNA demethylases of interest. Brittany Shimanski, a PhD student in the Chemistry-Biology Interface Program, uses these purified enzymes to study biochemistry and structural biology to better understand and target how eraser enzymes work. You have selected.

If Mugridge can form a complex with the modified RNA group on which the team acts to grow protein crystals, it will bring them to a national laboratory and take high-intensity X-rays to capture a 3D image of the shape of the enzyme. I explained that you can get. , Contains information about where all the atoms are and how the enzyme binds to methylated RNA.

This atomic-scale structural biology information provides important insights into how enzymes work, and how these scavenging enzymes are regulated by various proteins or small molecule cofactors such as vitamin C. It is also useful for studying Luke Calzini, a doctoral student to understand what you are doing. You can change their activity or selectivity.

This study also has the potential to give scientists new ways to ask specific questions within the cell.

“We feel that we are addressing important issues that may be important in understanding how different diseases work and are affected by changes in RNA methylation. “Mugridge says.

The new five-year project is funded through NIH’s Maximizing Investigators’ Research Award (MIRA) program.

Why the eraser enzyme doesn’t work and leads to cancer Why the eraser enzyme doesn’t work and leads to cancer

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