What You Need to Know n DNA is organized into small structures known as chromosomes. At the ends BIOTECH Basics of each chromosome are repeating sequences of DNA known as telomeres.

n Every time the cell divides and copies its DNA, the very end of the telomere is unable to be copied and the total telomere length is shortened. n Telomeres act as a buffer to protect the genes near the ends of the chro- mosome from being degraded by the Telomeres shortening process. the aglets of the genomic world n When the telomeres become too short, the cell stops dividing. This is called senescence and is associated hink about your fa- times. Telomere length varies between with aging. Tvorite pair of lace- individuals and across cell type but there up shoes. Focus on the may be as many as 15,000 nucleotides at n An enzyme known as telomerase is active in a small number of cells to keep shoelaces from those shoes, specifically the tip of a chromosome. telomeres long. Most adult cells have on the tips where the small plastic or met- When a cell divides, the chromosomes no telomerase present. al coverings wrap around the lace. Those are copied by specific enzymes and pro- coverings, known as aglets, protect the vide each daughter cell with a complete n There seems to be a link between long telomeres and longevity. Possibly ends from damage and keep the fibers set of genetic information. Unfortunately, those individuals who live long lives are of the lace from unraveling. If the aglet the copying enzymes are unable to com- producing a very low level of telom- wears away, the end becomes frayed and pletely reproduce the very end of each erase in their adult cells. it is time for the shoelace to be replaced. DNA strand, leading to a slightly shorter The image of a genetic aglet, a region copied fragment (for the science buffs n Continually active telomerase is a feature of many types of cancer, as at the end of a DNA strand that protects reading this article, this occurs at the 5’ it allows cells to divide indefinitely it from damage, serves as an appropriate end of the lagging strand). Damage from without reaching senescence. The level introduction to this edition of Biotech Ba- molecules known as free radicals also of telomerase activity must therefore sics. These regions, found at the tips of reduces the ends of the DNA in chromo- be balanced between slowing the signs chromosomes, are known as telomeres. somes. As a result, the copied strand is of aging and preventing the growth of A critical component of the genome, te- about 50-200 nucleotides shorter than tumor cells. lomeres have been implicated in both the original segment. Every time the cell cancer and aging. Recognizing the impor- divides, the chromosomes become short- tance of telomeres, the 2009 Nobel Prize er. Fortunately, the telomeres serve as a in Physiology or Medicine was awarded buffer region, absorbing the DNA reduc- to three scientists (Elizabeth Blackburn, tion without impacting those genes locat- For more information: Jack Szostak and Carol Greider) for the ed near the chromosome tip. discovery of telomere structure and iden- In humans, a small subset of actively tification of how telomeres function and dividing cells (such as those from bone Press release announcing the 2009 Nobel Prize in Physiology of Medicine: are maintained in cells. marrow, precursor sperm cells or most nobelprize.org/nobel_prizes/medicine/ stem cells) does not undergo telomere laureates/2009/press.html Structure and Function shortening. This is due to a remarkable This Web site has a well-written description Telomeres are repeating sequences enzyme known as telomerase that func- of telomeres and telomerase. of DNA found at the ends of each chro- tions to extend the telomere after every mosome (figure one). They help prevent cell division. Telomerase counteracts the Web page from the National Institutes chromosomes from fusing into rings or impact of DNA shortening and the telom- of Health describing the research binding haphazardly to each other. Pri- erase genes are present in every cell. connecting telomere length with longevity: marily found in plants and animals, te- During fetal development, telomerase is www.nih.gov/researchmatters/ november2009/11232009longevity.htm lomeres also protect chromosome ends active, resulting in long telomeres for all from damage. In humans, telomeres are the cells of the growing embryo. During composed of a six-nucleotide sequence the second trimester of pregnancy, the (TTAGGG) that is repeated thousands of telomerase genes are silenced across

4 most tissues, so the process of DNA or older) have longer than expected te- shortening begins. Telomerase remains lomeres and have given birth to children active at low levels among bone marrow with long telomeres. This suggests telom- Figure two and precursor sperm cells, maintaining ere length may be genetically controlled. long telomeres. When the telomere gene sequences were compared between the centenarians and Telomeres and Aging: populations that died at an earlier age, As an individual ages and undergoes several genetic differences were found. repeated cell divisions, the telomeres Preliminary findings suggest this genetic continue to shorten. At some point, the te- variation might allow silenced telomerase lomeres become so short that the genes genes to “whisper,” producing a small at the end of the chromosome are in dan- amount of telomerase expression. If low ger of being deleted. When this critical levels of telomerase are present in all The relationship between number of length is reached, a signal is activated cells throughout life, the repeated rounds cell divisions, activity of telomerase inside the cell to prevent further cell divi- of shortening may be delayed. In the lab- and telomere length sion (figure two). This process, known as oratory, telomerase has allowed cultures senescence, appears to be an important of human cells to grow and divide far be- online at hudsonalpha.org/education/out- factor in aging. Many scientists believe yond their normal limit. An alternative hy- reach/basics). A common finding among the physical signs of aging result from an pothesis is that long-lived individuals are different types of cancer is the presence ever-increasing proportion of cells reach- born with longer telomeres so the symp- of telomerase within the cancer cells. Re- ing senescence. Because fewer cells toms of aging are postponed. member, cancer cells experience cell di- are available to reproduce and replenish vision at a rapid pace. If telomeres were themselves, maintenance and defense of A role in cancer formation shortened with each round of division, the the body becomes difficult. In support of This begs the question: Could achiev- signal for senescence would be quickly this theory, a number of premature aging ing long life be as simple as reactivating reached. Tumors would never grow be- syndromes have been associated with the telomerase genes? It is not yet known yond a relatively small size because the short telomeres, although the precise if shorter telomeres are a cause of aging cell divisions would be halted. Instead, correlation between telomere length and or simply a visible sign of the aging pro- many cancer cells have acquired muta- disease symptoms is still unclear. cess. Mice, which live only a few years, tions that reactivate telomerase produc- Several other studies have confirmed have longer telomeres than humans, tion. These cells use telomerase to ex- a link between telomere length and long suggesting that telomere length is not the tend telomere lengths, allowing the tumor life. When scientists compared lifespan sole regulator of aging. In addition, there to continue its rapid growth. In light of this between two groups divided by telomere is a potential downside to producing te- finding, several research labs are explor- length, those with the longer telomeres lomerase throughout life, as it appears ing methods to silence telomerase in can- lived five years longer than those with to be a critical player in cancer. Cancer cer cells as a potential treatment option. shorter ones. An additional project found most often results from an accumulation The awarding of the Nobel Prize based that centenarians (individuals 100 years of genetic and environmental changes on telomere and telomerase research has that slowly convert brought renewed awareness and interest normal cells into ev- to this field of study. Telomeres play a Figure one er-growing tumors critical role: protecting our chromosomes (a previous Biotech and serving as a molecular “clock” with Basics article about respect to aging. cancer can be found A careful balance must be maintained with respect to telomerase activity. If te- lomerase is silenced too quickly, aging oc- curs prematurely. If telomerase remains active for too long, there is an increased risk of tumor formation. Research into At left: telomeres and their regulation will be a Telomeres. closely watched field for several years to (Credit: © The come. Nobel Committee for Physiology or – Dr. Neil Lamb Medicine 2009 / director of educational outreach Illustration: HudsonAlpha Institute for Biotechnology Annika Röhl)

THE SCIENCE OF PROGRESS 5