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
during development.
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 poortly 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.
