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 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.