Giuliana Fiorentino 10/20/11 Word Count: 1545 Role of Telomeres in the Premature Aging Disorder, Dyskeratosis Congenita The

human genome is a fascinating and delicate system. Within our forty-six chromosomes is a record of more than two-hundred-million years of evolution. We have developed a vast array of defense mechanisms to protect our cells from chromosomal errors. When one or more of these mechanisms fail, we call the resulting abnormality a genetic disorder. Genetic disorders arise from genetic mutations and range widely in severity. As a general rule of thumb, a greater the number of individual mutations results in more severe disorders. In the last ten years, there has been a rise in the research of telomeres, enzymes that mark the ends of chromosomes, because of their necessity for genetic stability. Muller and McClintock showed this approach to be fruitful in a series of studies from the 1930s through the 1940s (Chan, 2004). They demonstrated that a change in chromosome stability is the fundamental cause in premature-aging disorders. Dyskeratosis Congenita, or the premature failure of certain bone marrow functions, is a well-known example of a genetic disorder resulting from mutated TERC RNA. Scientists are attempting to find links between premature-aging disorders by studying mean telomere length, telomerase repair speed, and multi-generation cases of Dyskeratosis Congenita. Together, these studies are helping pinpoint what proteins (or lack of proteins) are responsible for premature-aging disorders. In order to better understand the genetic roots of DS, one must first understand why the affected gene is susceptible to degradation. Telomeres are protein-DNA molecules that are comprised of the repeated sequences of T-T-A-G-G-G. There are often over one-hundred iterations, or base pairs, of this sequence (Hartl, 2012). More specifically, telomerase is a reverse

transcription enzyme. It functions by adding the TTAGGG repeats to the strands of the DNA. Once the chain is extended, guide RNA, which contains the template for the complementary strange of DNA, lines up to allow for the attachment of complementary base pairs (Chan, 2004). During transcription and translation, segments of DNA are lost due to sticky ends. Sticky ends are caused by the RNA primers that initiate transcription. These single strands of DNA are often subject to degradation, as exonucleases cause chromosomes to shorten over time. Telomeres buffer and correct the losses caused by RNA primers. But if there is a missing sequence in its gene, the telomerase enzyme, which functions as a key to a lock, will be misshapen, resulting in less efficient telomeric activity (Chan, 2004). Providing an extra sequence on the end of chromosomes is not the only functions of telomeres. Telomeres also protect DNA by wrapping around certain telomere-binding proteins. This causes telomeric silencing, which ensures that genes in the telomere are not accidentally expressed (Hartl, 2012). In general, the more base pairs comprise the telomere, the more protected the chromosome. Therefore, telomeric shortening is generally bad. Dyskeratosis Congenita seems to show up consistently in cases of patients with mutations affecting any of the following proteins: dyskerin, TERC, TERT, NHP2, or NOP10 (Vulliamy, 2008). Most of these mutations directly affect the shape of telomerase, causing reduced efficiency. This usually results in shorter chains of tandem repeats, and the visible symptoms are of premature-aging disorders. Dyskeratosis Congenita, also known as Zinsser-Cole-Engman Syndrome, is a genetic aging disorder which often results in severe cases of bone marrow failure. Weakening of the bone marrow can lead to a number of possible illnesses, including pulmonary fibrosis, aplastic anemia, and especially cancer. People with a predisposition to cancer have to be especially careful. DC symptoms vary on a continuum and can sometimes be so mild as to be undiagnosed.

If a case is severe enough, DC can lead to reduced cerebellum size, directly affecting mental capability. Other minor physical symptoms include nail dystrophy and abnormal skin pigmentations. Theoretical scientists who are interested in the extension of life expectancy often study DC because of patients' characteristic premature cell-destruction. If these scientists are on the right track, in the near-to-distant future, we may be able to control of even reverse cell death, the ultimate cause of the aging process. In 1995, a different study was published using a more-controlled system of collecting data from live cultures. Scientists were able to use UV light to produce dimers in telomeres and track TRFL and mean DNA repair. Their results have showed that telomeres work hard to resist genetic errors caused by high-energy UV radiation impacting individual nucleic acids. This is could possibly be the function of the aforementioned telomeric silencing that occurs around the special telomere proteins (Chan, 2005). This implies that these proteins may have evolved as a sort of genetic radiation suit. Experimentation demonstrated that telomeres exposed to UV do not display reduced regeneration. Similarly, the mean length of the telomeres did not seem to be affected much by UV. As hypothesized, it was age, rather than radiation, that resulted in genetic degradation (Kruk, 1995). Old telomeres have more difficulty repairing themselves than their younger counterparts. As people age, their telomeres and telomerase become less efficient. This happens prematurely in the cells of people with Dyskeratosis Congenita. The results from this experiment were quite surprising to the scientific community and resulted in the funding of multiple labs to study the regenerative properties of telomeres more closely. One novel way in which scientists have researched premature-aging disorders was through the case-study of families with multiple generations of Dyskeratosis Congenita. This was accomplished by collecting blood samples from four generations of a family carrying DC

(Goldman, 2005). From there, scientists could track how the gene mutations were being expressed as unpleasant symptoms. It is useful to study genetic diseases in pedigrees because there are often multiple genes resulting in symptoms. In order to determine which genes were being affected, Goldman used PCR and determined that something was happening to the TERC gene. They labeled this TERC haploinsufficiency (Armanios, 2005). This is when the last 74 base pairs of the TERC RNA sequence are mysteriously deleted. This decreases the rate at which the telomerase works, resulting in a decrease in the length of the telomeres. Using this multi-generational case study, they were also able to determine the statistics of telomere restriction fragment lengths (TRFL). Previous studies have reported possible trends in telomere shortening. This had been interpreted as meaning that successive generations have shorter telomeres, but after this extensive journal it was decided that this was not the case at all; in fact telomere length is independent of the parental telomere length (Goldman, 2005). This study established the first ideas of DC being an autosomal-dominant genetic disorder making its development independent of sex. There are many recorded cases of patients with autosomal dominant, autosomal recessive, and X-linked Dyskeratosis Congenita, and so it is one of the most highly-studied of genetic aging disorders. It has been through generous research funding and much dedicated effort that we understand that this disorder is multigenic, or that multiple components of an individual's DNA are affected by each mutation. This was determined by a study done of telomeres in 2008. Vulliamy and his staff were able to identify five genes that are often mutated in patients with DC. More importantly, their study figured out which mutations cause the genetic subtypes to be X-linked, autosomal dominant, or autosomal recessive. Autosomal dominance was then determined to result in TERC haploinsufficiency. As mentioned above, this directly affects telomerase activity and reduces telomere length. The affected X-linked gene has a different potentially-mutated gene,

namely the DKC1 gene. This gene encodes dyskerin, a protein component of telomerase which, when lacking, reduces the telomere length. There have also been a few recorded cases of an autosomal-recessive subtype of DC. It is thought that, in these cases, the mutated NHP2 gene affects the TERC levels, but unfortunately experimentation has yet to confirm these results (Vulliamy, 2008). Telomere health has been highly researched in the last fifteen years due to its necessary role in chromosome stability. By understanding how and why DC causes cells to age more rapidly, scientists can begin to compose new experiments in which they attempt to age cells more slowly. The public needs to be made aware of the significant medical advances that telomase research can bring, including extending the life of cells or figuring out the mechanisms that control the growth of aggressive cancers. With continued public awareness, a wealth of donations and investments will inevitably bless these noble research projects, hopefully allowing growing research to proceed more quickly and stymied research to break through barriers. For example, it may be to necessary to develop methods for inhibiting different proteins within the DNA of less-commonly-studied animals with similar length telomeres to humans. The most commonly experimented-upon animal is the mouse, and it has been demonstrated that past studies are somewhat irrelevant, due to the fact that mice have much longer telomeres than humans. People are exposed to many harmful substances everyday, and this it is researchers duties to understand how our genetics are affected in the spectrum of genetic and chemical processes. The next questions that need to be answered are whether or not there are ways in which to artificially-supplement missing proteins or possibly correct specific mutations with gene therapy. The general public health depends on the next few decades of continued research.

Literature Cited
Armanios, M., Chen, J.-L., Chang, Y.-P. C., Brodosky, R. A., Hawkins, A., Griffin, C. A., . . . Grieder, C. W. (2005, November 1). Haploinsufficiency of Telomerase Reverse Transcriptase Leads to Anticipation in Autosomal Dominant Dyskeratosis Congenita. Proceedings of the National Academy of Sciences of the United States of America, 102(44), 15960-15964. Retrieved from http://www.jstor.org/stable/4143307

Chan, S. R., & Blackburn, E. H. (2004, January 29). Telomeres and Telomerase. Philosophical Transactions: Biological Sciences, 359(1441), 109-121 . Retrieved from http://www.jstor.org/stable/4142286

Goldman, F., Bouarich, R., Kulkarni, S., Freeman, S., Du, H.-Y., Harrington, L., . . . Bessler, M. (2005, November 22). The Effect of TERC Haploinsufficiency on the Inheritance of Telomere Length. Proceedings of the National Academy of Sciences of the United States of America, 102(47), 17119-17124 . Retrieved from http://www.jstor.org/stable/4152362 Hartl, D. L., & Ruvolo, M. (2012). Molecular Structure of the Telomere. In Genetics Analysis of Genes and Genomes (8th ed., pp. 246-251). Burlington, MA: Jones and Barlett Learning. Kruk, P. A., Rampino, N. J., & Bohr, V. A. (1995, January 3). DNA Damage and Repair in Telomeres:Relation to Aging. Proceedings of the National Academy of Sciences of the United States of America, 92(1), 258-262. Retrieved from http://www.jstor.org/stable/2366539 Vulliamy, T., Beswick, R., Kirwan, M., Marrone, A., Digweed, M., Walne, A., & Dokal, I. (2008, June 10). Mutations in the Telomerase Component NHP2 Cause the Premature Ageing Syndrome Dyskeratosis Congenita. Proceedings of the National Academy of Sciences of the United States of America, 105(23), 8073-8078 . Retrieved from http://www.jstor.org/stable/25462733