PNAS scientists have discovered messenger RNA with dual functions

A study led by Julian Chen and his team at the Center for Evolutionary Mechanisms at Arizona State University's School of Molecular Sciences and the Biodesign Institute has first discovered an unprecedented pathway
to generating telomerase RNA from protein-coding messenger RNA (mRNA).

The central teachings of molecular biology dictate the sequence
in which genetic information is transferred from DNA to the manufacture of proteins.
Messenger RNA molecules carry genetic information from DNA in the nucleus to the cytoplasm
that makes proteins.
Messenger RNA acts as messengers to build proteins
.

"Actually, there's a lot of RNA (RNA) that isn't used to make proteins," Chen explains
.
"About 70 percent of the human genome is used to make non-coding RNAs that don't code for protein sequences but have other uses
.
"

Telomerase RNA is a non-coding RNA that assembles together with telomerase proteins to form telomerase
.
Telomerase is essential
for the immortality of cancer cells and stem cells.
In this study, Chen's team showed that fungal telomerase RNA is processed from mRNA encoding proteins, rather than synthesized independently
.

"What we find in this paper is a paradigm shift
.
Most RNA molecules are synthesized independently, and here we found a dual-function mRNA that can be used to produce proteins or make non-coding telomerase RNA, which is really unique
.
"We need to do more research to understand the underlying mechanisms
of this unusual RNA biogenesis pathway.
"

Basic research on mRNA metabolism and regulation has led to important medical applications
.
For example, some COVID-19 vaccines use messenger RNA as a means of
producing viral spike proteins.
In these vaccines, the mRNA molecules are eventually degraded and then absorbed
by our bodies.

This new approach has advantages over DNA vaccines, which have the potential risk of harming and permanently integrating into our DNA
.
Dual-function mRNA biogeneration was discovered in this work, which could lead to innovative approaches
to mRNA vaccines in the future.

In this study, Chen's team accidentally discovered mRNA-derived telomerase RNA in the model fungal biobio Maize Smut fungus
.
Corn smut, also known as Mexican truffles, is edible and adds a delicious umami effect to many dishes, such as tamales and tamales
.
Through the study of maize smut RNA and telomere biology, it
is possible to explore new mechanisms of mRNA metabolism and telomerase biogenesis in maize smut disease.

Why study telomerase RNA?

The 2009 Nobel Prize in Physiology or Medicine was awarded to "Discover How Chromosomes Are Protected by Telomeres and Telomerase"
.
For the first time, telomerase was
isolated from single-celled organisms living in pond scum.
It was later discovered that telomerase is present in almost all eukaryotes, including humans, and plays a vital role
in aging and cancer.
Scientists have been working hard to find ways
to use telomerase to make human cells immortal.

Typical human cells die and cannot renew
themselves forever.
As Leonard Hayflick demonstrated half a century ago, the replication lifespan of human cells is limited, and older cells reach this limit
earlier than younger cells.
This "Hayflick limit" of cell lifespan is directly related
to the number of unique DNA replicates found at the chromosomal ends that carry the genetic material.
These DNA duplications are part of a protective cap-like structure called "telomeres" that protect chromosomal ends from unnecessary and irrational DNA rearrangements, thereby destabilizing
the genome.

Every time a cell divides, telomere DNA contracts and eventually fails to hold the chromosomal end.

The constant reduction in telomere length, like a "molecular clock", can be counted down to the end
of cell growth.

The weakening of the ability of cells to grow is closely related to the aging process, and the reduction of the number of cells directly leads to weakness, disease and organ failure
.
It is telomerase that fights the telomere contraction process, and this enzyme is the only key
to delaying or even reversing the process of cellular aging.
Telomerase counteracts cellular senescence by lengthening telomeres, adding lost DNA repeatedly to the countdown to the molecular clock, effectively extending the life
of cells.

Telomerase lengthens telomeres by repeating a very short DNA repeating sequence of 6 nucleotides (components of DNA), the sequence "GGTTAG" located at the chromosomal end
on a template in the enzyme's own RNA component.

The gradual shrinkage of telomeres can negatively affect the ability of human stem cells to replicate, which can repair damaged tissues and/or replenish aging organs
in our bodies.
The activity of telomerase in adult stem cells only slows down the countdown to the molecular clock and does not make these cells completely immortal
.
Therefore, adult stem cells are depleted in the elderly due to the degeneration
of organ tissues due to increased healing time due to the shortening of telomere length and insufficient number of cells.

Take full advantage of the potential of telomerase

Understanding the regulation and restriction of telomerase promises to reverse telomere shortening and cell aging, and potentially extend human lifespan and improve health in
older adults.

Human diseases such as congenital keratosis, aplastic anemia, and idiopathic pulmonary fibrosis are all associated
with mutations that negatively affect telomerase activity and/or accelerate telomere length loss.
This accelerated telomere shortening is very similar to premature aging, with increased organ deterioration and a severe shortage of stem cells resulting in a shortened
patient lifespan.
Increasing telomerase activity appears to be the most promising way to
treat these genetic disorders.

While an increase in telomerase activity can rejuvenate senescent cells and treat diseases of premature aging, too many good things can cause harm
to individuals.
Just as young stem cells use telomerase to compensate for the loss of telomere length, cancer cells also use telomerase to maintain their abnormally destructive growth
.
Enhancing and regulating the function of telomerase will have to be performed precisely, walking a tightrope
between cell regeneration and an increased risk of cancer development.

Unlike human stem cells, somatic cells make up the vast majority of human cells and lack telomerase activity
.
Telomerase deficiency in human somatic cells reduces the risk of cancer development because telomerase promotes the uncontrolled growth
of cancer cells.
Therefore, drugs that indiscriminately increase telomerase activity in all cells are not advisable
.
Small molecule drugs can be screened or designed specifically to increase telomerase activity within stem cells for disease treatment and anti-aging treatment without increasing cancer risk
.

Research into the biogenesis of maize smut telomerase RNA may reveal new mechanisms of telomerase regulation and provide new directions
for the regulation or engineering of human telomerase for the innovative development of anti-aging and anti-cancer therapies.

The study, titled "The Biogenesis of Extracting Telomerase RNA from Protein-Encoded mRNA Precursors," has just been published in PNAS
.
The team at Arizona State University includes first author postdoc Dhenugen Logeswaran and former research assistant professor Li, PhD student Khadiza Akhter, former postdoc Joshua Podlevsky (currently at Sandia National Laboratory in Albuquerque, New Mexico) and two undergraduate students, Tamara Olson and Katherine Fosberg
.

Dhenugen Logeswaran, Yang Li, Khadiza Akhter, Joshua D.
Podlevsky, Tamara L.
Olson, Katherine Forsberg, Julian J.
-L.
Chen.
Biogenesis of telomerase RNA from a protein-coding mRNA precursor.
Proceedings of the National Academy of Sciences, 2022; 119 (41)