Upload new images. The image library for this site will open in a new window.
Upload new documents. The document library for this site will open in a new window.
Show web part zones on the page. Web parts can be added to display dynamic content such as calendars or photo galleries.
Choose between different arrangements of page sections. Page layouts can be changed even after content has been added.
Move this whole section down, swapping places with the section below it.
Check for and fix problems in the body text. Text pasted in from other sources may contain malformed HTML which the code cleaner will remove.
Accordion feature turned off, click to turn on.
Accordion featurd turned on, click to turn off.
Change the way the image is cropped for this page layout.
Cycle through size options for this image or video.
Align the media panel to the right/left in this section.
Open the image pane in this body section. Click in the image pane to select an image from the image library.
Open the video pane in this body section. Click in the video pane to embed a video. Click ? for step-by-step instructions.
Remove the image from the media panel. This does not delete the image from the library.
Remove the video from the media panel.
University of Delaware Assistant Professor Jeff Mugridge is
studying eraser enzymes that can remove important chemical groups from
mRNA, the molecules in our bodies that carry instructions and code to
tell our cells how to function. The work has the potential to inform
treatment options for various human diseases where these eraser enzymes
University of Delaware biochemist Jeff Mugridge is trying to figure
out how so-called mRNA eraser enzymes work in our cells, why those
erasers can sometimes misbehave and lead to cancer, and how science can
pave the way for possible solutions to this problem.
Ribonucleic acid (RNA) is a single-stranded molecule that is copied
from the DNA in our bodies. Messenger RNA (mRNA) molecules carry the
instruction code that tells our cells how to do everything they need to
survive, such as when, where and how to make proteins or enzymes.
One of the many ways the cells in our bodies control mRNA molecules
is to decorate them with different chemical groups that either subtly or
drastically change the way that messages are conveyed.
Mugridge, assistant professor of chemistry and biochemistry,
was recently awarded $1,956,466 from the National Institutes of Health
(NIH) to study specific enzymes that can act like erasers and remove
critical chemical groups, called methyl groups, found on mRNA molecules.
With hard-to-treat cancers like glioblastoma, sometimes these methyl
eraser enzymes are overexpressed in cancer cells — meaning too many
eraser enzymes are working at once. This can cause mRNA molecules to
lack important information, which can change the messages they deliver
in a way that leads to cancer progression and tumor growth.
Little is known about how these eraser enzymes decide which methyl
groups to eliminate or keep, how often they erase methyl groups in
healthy cells or why they misbehave in some human diseases.
Move this whole section up, swapping places with the section above it.
Along with two doctoral students working in his lab, Mugridge is
specifically looking at a class of eraser enzymes called RNA
demethylases. Demethylases remove methyl groups on RNA that play
important roles in gene expression and the progression of cancers like
glioblastoma or acute myeloid leukemia.
RNA methylation is a biochemical process that can act like a switch
and turn certain activities on or off in our cells. It is known to be
important for producing properly shaped RNA molecules, synthesizing
proteins and determining the lifespan of RNA molecules in the cell,
among other things. Methyl modifications on mRNA also play a role in
cell fate decisions and the way embryonic stem cells are differentiated
Scientists have recently identified a few RNA methyl modification
erasers, which has raised the intriguing possibility that these methyl
groups can be both written and erased from an mRNA transcript, Mugridge
said. But how these eraser enzymes recognize and choose which specific
methyl groups to remove out of the thousands that are found on RNA, and
how frequently they do this, remains poorly understood.
Does it happen all the time, or is it a rare event? Does it only
happen in disease or in specific cell types? These are some of the
questions Mugridge and his team plan to answer. The research team also
will explore how proteins and other cofactors, such as vitamin C,
regulate demethylase activity in the cell.
“Long-term, if we have a high-resolution picture of how these
demethylase enzymes work, then we can begin to understand how each
eraser is linked to different human diseases and disease progression,”
said Mugridge. “This will give us better information about which of
these enzymes to target for inhibition and how, for example, to slow
down tumor progression in cancer.”
For instance, in glioblastoma an eraser enzyme known as FTO is
overexpressed, meaning the glioblastoma cells make much more of it
compared to normal cells. This leads to a lot of methyl-erasing activity
on RNA in those cancer cells, which seems to be important for cancer
progression. Research has shown that when FTO is inhibited with a drug,
it slows down cancer progression in glioblastoma. However, therapeutics
that can selectively and effectively target RNA demethylase enzymes to
treat cancers have eluded scientists.
If Mugridge and his team can figure out the molecular details of how
these demethylase enzymes work and how the cell controls their
functions, they could look for ways to manipulate which methyl groups
get erased from RNA and pave the way for therapeutics that help correct
misbehaving eraser enzymes in disease.
“If we understood how the RNA molecule binds, exactly where it binds
on the protein surface and how it interacts with specific amino acids
that make up the protein, we might be able to fill in the missing pieces
of the puzzle and then develop tools to monitor or influence this
erasing activity in cells,” he said.
In Brown Laboratory, Mugridge and his students produce proteins in
bacterial cells and then purify and isolate the specific RNA
demethylases of interest. Brittany Shimanski, a doctoral student from
the Chemistry-Biology Interface program,
is using these purified enzymes to conduct biochemistry and structural
biology studies to better understand how the eraser enzymes function and
select their targets.
Mugridge explained that if the team can grow crystals of the proteins
in complex with the modified RNA groups that they act on, they can take
them to a national lab and shoot them with high-intensity X-rays to get
3D images of the enzyme’s shape, including information about where all
the atoms are located and how the enzymes bind to the methylated RNA
that they are going to erase.
This atomic-scale structural biology information can provide critical
insights into how an enzyme works and will also inform doctoral student
Luke Calzini’s work to understand how these eraser enzymes are
controlled by different proteins or small-molecule co-factors, such as
vitamin C, that can change their activity or selectivity.
The work could give scientists new ways to ask specific questions in cells, too.
“We feel like we’re working on an important problem that could be
significant for understanding how different diseases work and how they
are impacted by changes in RNA methylation,” said Mugridge.
The new five-year project is funded through NIH’s Maximizing Investigators’ Research Award (MIRA) program.
Article by Karen B. Roberts;
Photo by Evan Krape; Photo illustration by Jeffrey C. Chase
Published November 22, 2021