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The Center for the Mechanism of Evolution at the Biodesign Institute and the School of Molecular Sciences at Arizona State University, under the direction of Julian Chen, have for the first time found an unheard-of route that converts a messenger RNA that codes for protein into telomerase RNA (mRNA). The fundamental tenet of molecular biology lays forth the sequence in which genetic material is transmitted 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.

In actuality, a large number of RNAs (ribonucleic acids) are not required for the production of proteins. The production of non-coding RNAs, which serve purposes other than encoding protein sequences, takes up around 70% of the human genome. Julian Chen, the Center for the Mechanism of Evolution at the Biodesign Institute, and the School of Molecular Sciences at Arizona State University One of the non-coding RNAs that comes together with the telomerase proteins to generate the enzyme telomerase is telomerase RNA. For cancer and stem cells to be immortal, telomerase is essential. According to this discovery by Chen’s team, a fungal telomerase RNA is processed from a protein-coding mRNA rather than being produced separately.

“This research presents paradigm-shifting findings. We discovered a dual function mRNA that can be used to build a protein or a non-coding telomerase RNA, which is highly unusual because most RNA molecules are synthesized independently, said Chen. To comprehend the underlying mechanism of such an uncommon RNA synthesis process, we will need to conduct a great deal more research.

There are significant medical applications resulting from basic research on the metabolism and regulation of mRNA. For instance, a number of COVID-19 vaccines manufacture viral spike proteins using messenger RNA. The mRNA molecules in these vaccines gradually deteriorate and are then taken up by our bodies. Compared to DNA vaccinations, which carry the risk of becoming permanently and negatively incorporated into human DNA, this new technique has advantages. This work’s finding of dual-function mRNA biogenesis may inspire new approaches to the development of mRNA vaccines in the future.

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In this study, Chen’s team found the unexpected telomerase RNA in the model fungus Ustilago maydis, also known as maize smut. Eating corn smut, also known as Mexican truffle, gives many foods, such tamales and tacos, a delightful umami flavor. Finding new pathways for mRNA metabolism and telomerase biogenesis may be possible by studying the biology of RNA and telomeres in corn smut. The 2009 Nobel Prize in Physiology or Medicine was given “for the discovery of how telomeres and the enzyme telomerase safeguard chromosomes.” First discovered in a unicellular creature found in pond slime, telomerase. As it turns out, telomerase is a critical component of aging and cancer and is present in practically all eukaryotic creatures, including humans. In an effort to make human cells everlasting, 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 closely 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 unwelcome and unjustified DNA rearrangements that could destabilize the genome.

The telomeric DNA gets smaller with each cell division and eventually stops holding the chromosomal ends together. This ongoing shortening of telomeres serves as a “molecular clock” that keeps track of when cell growth will come to a stop. The aging process is closely linked to cells’ limited capacity to grow, and the decreased cell population directly contributes to organ failure, disease, and frailty. 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 lengthening the telomeres and re-adding missing DNA repeats to the molecular clock countdown, telomerase successfully extends the life of the cell and counteracts cellular aging.

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The process by which telomerase lengthens telomeres involves repeatedly synthesizing very brief DNA repetitions of six nucleotides, or the building blocks of DNA, onto the ends of chromosomes using a template found inside 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 just delays the molecular clock’s countdown; it does not entirely immortalize these cells. Therefore, telomere length shortening causes adult stem cells to become depleted in older people, which causes longer healing durations and organ tissue deterioration from insufficient cell populations.

With the capacity to reverse telomere shortening and cellular aging, understanding the regulation and restriction of the telomerase enzyme holds the possibility of extending human life expectancy and enhancing the wellbeing of the elderly. Genetically altered telomerase activity and/or accelerated telomere length loss have been related to a number of human disorders, such as dyskeratosis congenita, aplastic anemia, and idiopathic pulmonary fibrosis. This rapid telomere shortening, which is brought on by critically insufficient stem cell populations, closely resembles premature aging with greater organ degeneration and a shorter patient life span. The most promising approach to addressing these hereditary illnesses appears to be increasing telomerase activity.

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 require telomerase to maintain their abnormal and harmful growth, much as young stem cells do to counteract telomere length reduction. A fine line must be drawn between cell rejuvenation and an increased risk of cancer development when regulating and enhancing telomerase action.

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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 proliferation. Drugs that indiscriminately boost telomerase activity in all cell types are therefore undesirable. For the treatment of diseases and anti-aging therapies, small molecule medicines can be tested or created to boost telomerase activity exclusively within stem cells without raising the danger of malignancy.

The investigation of telomerase RNA biosynthesis in corn smut may reveal novel regulatory mechanisms for telomerase and provide fresh perspectives on how to create or tune human telomerase for novel anti-aging and anti-cancer treatments. In the most recent issue of the Proceedings of the National Academy of Sciences, this work, 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. 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 invested in our research and spent a lot of time in the lab.

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