Under the direction of Julian Chen, the Center for the Mechanism of Evolution at the Biodesign Institute and the School of Molecular Sciences at Arizona State University have for the first time found an unheard-of pathway that converts a messenger RNA that codes for protein into telomerase RNA (mRNA).
The fundamental tenet of molecular biology lays out the sequence in which genetic material is transferred from DNA to proteins to produce proteins. Messenger RNA molecules transport genetic data from the DNA in the cell’s nucleus to the cytoplasm, which is where proteins are produced. The messenger used to create proteins is messenger RNA.
According to Chen, a lot of RNAs (ribonucleic acids) aren’t necessary for the production of proteins. The production of noncoding RNAs, which serve other purposes but do not code for protein sequences, takes up about 70% of the human genome.
One of the non-coding RNAs that comes together with the telomerase proteins to form the enzyme telomerase is telomerase RNA. Telomerase is essential for cancer and stem cells to remain immortal. According to this study by Chen’s team, a fungal telomerase RNA is processed from a protein-coding mRNA rather than being synthesized separately.
This paper presents a paradigm-shifting conclusion. “The majority of RNA molecules are created separately, but in this study, we discovered a dual-function mRNA that can be used to make either a non-coding RNA or a protein,” added Chen. We will need to do a lot more research in order to figure out how such an unusual RNA biogenesis pathway works.
There are significant medical applications resulting from basic research on the metabolism and regulation of mRNA. For instance, a number of COVID-19 vaccines produce viral spike proteins using messenger RNA. The mRNA molecules in these vaccines break down over time, and then our bodies take them in.
Compared to DNA vaccines, which carry the risk of becoming permanently and negatively incorporated into our DNA, this new approach has advantages. The discovery of dual-function mRNA biogenesis in this work could help scientists come up with new ways to make mRNA vaccines in the future.
In this study, Chen’s team found that the model fungus Ustilago maydis orcorn smut contained an unexpected mRNA-derived telomerase RNA. Eating corn smut, also known as Mexican truffle, gives many dishes, like tamales and tacos, a delicious umami flavor. By looking at how RNA and telomeres work in corn smut, scientists might be able to find new ways to make mRNA and telomerase.
Why study telomerase RNA?
The 2009 Nobel Prize in Physiology or Medicine was given “for the discovery of how telomeres and the enzyme telomerase protect chromosomes.” first discovered in a unicellular organism found in pond scum, telomerase. As it turned out, telomerase is a critical component of aging and cancer and is present in almost all eukaryotic organisms, including humans. In an effort to make human cells immortal, scientists have been working feverishly to find ways to use telomerase.
Normal human cells are transient and cannot perpetually regenerate. Human cells have a finite reproductive life span, which is reached earlier in older cells than in younger cells, as Leonard Hayflick showed fifty years ago. The number of distinct DNA repeats discovered at the ends of the genetic material-bearing chromosomes is directly related to the “Hayflick limit” of cellular life span. These DNA repeats are a component of the “telomeres,” which are protective capping structures that guard the ends of chromosomes from unwanted and unjustified DNA rearrangements that could destabilize the genome.
The telomeric DNA gets smaller with each cell division and eventually stops holding the chromosome ends together. This ongoing shortening of telomeres serves as a “molecular clock” that keeps track of when cell growth will come to an end.
Aging is closely linked to cells losing their ability to grow, and a smaller number of cells leads directly to organ failure, illness, and weakness.
The enzyme telomerase, which is unique in holding the key to postponing or even reversing the cellular aging process, works to counteract the shrinking of telomeres. By making the telomeres longer and adding back missing DNA repeats to the molecular clock, telomerase effectively extends the life of the cell and stops it from getting older.
By repeatedly synthesizing very brief DNA repeats of six nucleotides, the DNA molecule’s building blocks, with the sequence “GGTTAG” onto the ends of chromosomes, telomerase lengthens telomeres. This is done using a template that is found within the RNA component of the enzyme.
Human stem cells, which repair damaged tissues and/or replenish aging organs in our bodies, are negatively impacted by the progressive shortening of telomeres. Telomerase activity in adult stem cells only slows the molecular clock’s countdown; it does not completely immortalize these cells. So, as telomeres get shorter, adult stem cells become depleted in older people. This makes healing take longer and causes organ tissue to break down because there aren’t enough cells.
Tapping the full potential of telomerase
Understanding how the telomerase enzyme is controlled and limited could help people live longer and be healthier as they age by stopping telomeres from getting shorter and slowing down the aging of cells.
Genetically altered telomerase activity and/or accelerated telomere length loss have been linked to a number of human diseases, such as dyskeratosis congenita, aplastic anemia, and idiopathic pulmonary fibrosis. This accelerated telomere shortening, which is brought on by critically insufficient stem cell populations, closely resembles premature aging with increased organ deterioration and a shorter patient life span. Increasing telomerase activity seems to be the most promising way to treat these genetic diseases.
Increased telomerase activity has the potential to rejuvenate aging cells and treat conditions that mimic premature aging, but too much of a good thing can be harmful to the body. Cancer cells use telomerase to maintain their abnormal and harmful growth, just as young stem cells do to counteract telomere length loss. When regulating and improving telomerase function, there is a thin line that must be drawn between cell rejuvenation and an increased risk of cancer.
Somatic cells, which make up the vast majority of the cells in the human body and differ from human stem cells by not having telomerase activity, Human somatic cells lacking telomerase have a lower chance of developing cancer because telomerase promotes unchecked cancer cell growth. Drugs that indiscriminately boost telomerase activity in all cell types are therefore undesirable. Small molecule drugs can be tested or made to increase telomerase activity only in stem cells without increasing the risk of cancer. This can help treat diseases and slow the aging process.
The study of how telomerase RNA is made in corn smut could reveal new ways that telomerase is controlled and give new ideas about how to engineer or change human telomerase to make new anti-aging and anti-cancer drugs.
In the most recent issue of the Proceedings of the National Academy of Sciences, this study, titled “Biogenesis of telomerase RNA from a protein-coding mRNA precursor,” was presented. The ASU team also includes two undergraduate students, Tamara Olson and Katherine Fosberg, as well as the first author postdoc, Dhenugen Logeswaran, former research assistant professor Yang Li, doctoral student Khadiza Akhter, former postdoc Joshua Podlevsky (now at Sandia National Labs in Albuquerque, New Mexico), and two graduate students, Khadiza Akhter and Amina Ali.
Tamara Olson and Katherine Fosberg, two undergraduates from ASU who spent more than a year working in Chen’s lab, also received praise from Chen for their abilities. They were deeply involved in our research and spent a lot of time in the lab.
