Tracking the lifespan and myriad functions of mRNA

Date:
January 19, 2022
Source:
Yale University
Summary:
New studies shed light on how mRNAs are born and how they regulate
production of proteins inside of our cells once they reach
maturity. The findings have implications not only for achieving
effective doses for new vaccines, but for helping determine the
biological roots of many cancers and diseases.



FULL STORY ==========================================================================
It took a global pandemic, but the critical role of messenger RNA in
all of life's functions has taken center stage in the past year with
the successful rollout of mRNA vaccines to combat the SARS-Cov-2 virus.


==========================================================================
In two new papers published the week of Jan. 17, the lab of Yale's
Wendy Gilbert sheds light on how mRNAs are born and how they regulate production of proteins inside of our cells once they reach maturity. The findings have implications not only for achieving effective doses for
new vaccines, but for helping determine the biological roots of many
cancers and diseases.

"It's been exciting to be able to study the beginning and end of this
process," said Gilbert, associate professor of molecular biophysics
and biochemistry.

In classic textbook biology, cells precisely copy or transcribe genes
encoded in DNA into mRNAs, which then ferry those instructions to the
ribosome, the machinery within the cell that makes the proteins that
carry out almost all life functions. This key role played by mRNA
has made the molecule a major research target for decades, including
research that led to the rapid development of mRNA vaccines in the fight against COVID-19. The vaccines developed by Pfizer and Moderna contain mRNA-based instructions for cells to produce proteins that recognize
spike proteins on the surface of the SARS-Cov- 2 virus, making them
targets for destruction by the immune system.

While RNA is formed from just four bases, or nucleotides, its structure
and function can be altered by complex biochemical interactions
with other compounds. One such compound that modifies mRNA is
pseudouridine, an isomer whose presence is a key to the effectiveness
of mRNA vaccines. Even before the pandemic, Gilbert's lab discovered
the presence of pseudouridine in normal cellular mRNA. At the time, she
became curious about how exactly these mRNA modifications are created
and how they affect the mRNA's function.

In one of the new studies, a team led by Nicole Martinez, a postdoctoral
fellow in Gilbert's lab, found that pseudouridine plays a key role in the genesis of mRNAs. The team found pseudouridine present at the earliest
stages of the formation of mRNAs. And the researchers discovered evidence
that it guides the splicing of genetic material that creates mRNAs,
which in turn regulate gene activity, they report Jan. 19 in the journal Molecular Cell.

These findings shed new light on origins of diseases linked to variants
of pseudouridine such as mitochondrial myopathy, digestive disorders, intellectual disability, and resistance to viral infection. For instance, several cancers have been linked to elevated levels of pseudouridine, suggesting that faulty splicing of mRNAs may trigger tumor formation
and cancer metastasis.

In a second paper, published Jan. 17 in the journal Cell Systems, Yale researchers investigated just how it is that ribosomes know how many
proteins to produce from the genetic instructions they receive from
mRNAs. For the study, a team headed by Rachel Niederer, an associate
research scientist in Gilbert's lab, developed new technology called
direct analysis of ribosome targeting (DART) to find regulatory
elements that can spur and silence the production of proteins by
ribosomes. Manipulating such elements in mRNAs -- in this case, within
yeast -- allowed scientists to modify production of proteins by a thousand-fold, they report.

The ability to precisely manipulate protein production has immediate applications in adjusting doses in mRNA vaccines such as those used to
combat COVID, the researchers say. Their work led to a $1.7 million grant
from Pfizer to the Gilbert lab and that of Carson Thoreen, associate
professor of cellular and molecular physiology at Yale.

Gilbert stressed, however, that the technology could also be applied to development of any protein-based therapies for a multitude of diseases.

========================================================================== Story Source: Materials provided by Yale_University. Original written
by Bill Hathaway. Note: Content may be edited for style and length.


========================================================================== Journal References:
1. Nicole M. Martinez, Amanda Su, Margaret C. Burns, Julia
K. Nussbacher,
Cassandra Schaening, Shashank Sathe, Gene W. Yeo, Wendy V. Gilbert.

Pseudouridine synthases modify human pre-mRNA co-transcriptionally
and affect pre-mRNA processing. Molecular Cell, 2022; DOI: 10.1016/
j.molcel.2021.12.023
2. Rachel O. Niederer, Maria F. Rojas-Duran, Boris Zinshteyn, Wendy V.

Gilbert. Direct analysis of ribosome targeting illuminates
thousand-fold regulation of translation initiation. Cell Systems,
2022; DOI: 10.1016/ j.cels.2021.12.002 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220119121442.htm

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