By Joel C. Eissenberg, Ph.D.
Published in Missouri Medicine, the Journal of the Missouri State Medical Association, February/March 2013
If we could induce our somatic cells to express significant amounts of telomerase, would we live longer? The evidence based on studies of human cells in culture makes this appear possible.
“I’m not afraid of death; I just don’t want to be there when it happens.”
– Woody Allen
“Immortality is a long shot, I admit. But somebody has to be first.”
– Bill Cosby
Like our clothes, our chromosomes fray at the edges with age. Some believe that if we could discover a molecular tailor to patch our age-abraded chromosome ends, we could become modern Methuselahs. Notably, cancer cells achieve immortality by protecting their chromosome ends. Drugs that selectively fray the ends of cancer cell chromosomes would be potent and general anti-cancer therapies.
Here, I summarize data on the role of chromosome ends in cellular and organismal aging.
One of the big surprises to emerge from the human genome project was the fact that less than 3% of our DNA encodes our genes. While the purpose—if any—of most noncoding DNA is still being determined, the function of some of this gene-free DNA has long been known to be important in preserving our chromosomes during the cell divisions that occur during the normal wear and tear of age and during wound repair after injury. Each of our chromosomes contains three DNA sequences that are key to maintaining healthy chromosome numbers and structure during our lifetimes. One of these sequences defines the centromere, which helps assure that each chromosome is properly sorted at cell division. The other two sequences occur at each end of the chromosome. These sequences define protective caps called telomeres (See Figure 1).
The geneticist Hermann Muller (Nobel Prize in Physiology or Medicine, 1946) noted the peculiarity of chromosome ends in the course of his work on the genetic effects of ionizing radiation in the fruit fly Drosophila melanogaster. He found that X-irradiation caused chromosome breaks that were repaired by fusing the several newly broken ends together, often in abnormal combinations. Strikingly, though, the new chromosome ends created by X-ray-induced chromosome breakage were never repaired by fusion with the naturally occurring ends of chromosomes. From many such studies, Muller concluded that the natural ends of chromosomes were somehow special, and he called these special structures “telomeres,” from the Greek telos, meaning “end” and meros, meaning “part.”1
At around the same time, Barbara McClintock (Nobel Prize in Physiology or Medicine, 1983) noticed a similar property in the chromosomes of corn. In these studies, the new DNA breaks were caused by the transposable elements that she later became famous for discovering. As with X-rays, though, the new chromosome ends at the sites of breaks only rejoined with one another and never with the naturally occurring ends of chromosomes.2.3
Thus, telomeres somehow disguise the ends of chromosomes from each other and from new DNA breaks. All organisms with linear chromosomes, from fungi to plants to animals, have telomeres. The chromosomes of bacteria, which lack telomeres, are circular and so have no ends to protect.
When James D. Watson and Francis Crick solved the double helical structure of DNA, they noted that the structure suggested a mechanism for DNA replication. Their prediction was borne out in much subsequent research on DNA replication biochemistry, but the mechanistic details of replication create a problem for linear chromosomes. Because of limitations in DNA polymerase enzymology and the orientation of the DNA strands in the double helix, it is impossible to make complete copies of both DNA strands at each end of linear DNA molecules. Thus, with each cell division, the biochemistry of replication dictates that chromosomes should gradually shorten from each end. This conundrum is called the “end replication problem.” However, the fact that so many living organisms have maintained linear chromosomes testifies to nature’s ability to solve this problem.
With the advent of DNA sequencing technology in the 1970s, it soon became apparent that the DNA sequences at chromosomes ends are distinctive, consisting of tandem repeats of short sequence motifs. The number of repeats and the sequence of the repeated motif differ between organisms, but the basic repetitious structure is found for telomeres of fungi, protozoa and most animals including humans. Since these sequences don’t encode genes, they can be lost without eroding the genetic information carried by the rest of the chromosomal DNA. Additionally, detailed genetic and biochemical studies, primarily using yeast, have shown that the repeated sequences at the end of chromosomes bind to specialized proteins that help conceal the natural ends of chromosomal DNA so that they don’t resemble broken DNA.
This protein “cap” explains why Muller and McClintock never saw telomeres fuse with other DNA breaks. It also explains another biological puzzle. DNA breaks normally cause dividing cells to arrest. This arrest provides a window of opportunity for the cell to repair the break before the onset of the next cell division, which otherwise could result in chromosome fragments being mis-sorted or lost. If repair takes too long, the damaged cells will initiate “apoptosis,” or programmed cell death. The caps on telomeres prevent dividing cells from seeing their own chromosome ends as DNA breaks, permitting normal cell division to proceed.
But telomere repeats and their associated caps don’t actually solve the end replication problem. The answer to this proved to be a novel DNA replication biochemistry uncovered by Elizabeth Blackburn, Jack Szostak and Carol Greider, who shared the Nobel Prize in Physiology or Medicine in 2009 (See Figure 2). Using the peculiar biology of a ciliated protozoan, Tetrahymena thermophila, the versatile genetics of the yeast Saccharomyces cerevisiae and the classical toolkit of enzymology, these scientists discovered an enzyme that could add new DNA sequence to chromosome ends, reversing the erosion due to incomplete replication by the standard DNA replication pathway. Remarkably, this enzyme uses RNA, a type of molecule usually made as a copy of DNA sequence, as a blueprint to make new DNA sequences at telomeres. The RNA blueprint is short, but it is copied over and over, creating the characteristic tandem repeat sequences of telomere DNA. In biochemistry, an enzyme name usually has the suffix –ase added to the process it controls, so the telomere-adding enzyme was called “telomerase.”
The importance of telomerase in human health is underscored by the clinical presentation of patients with genetic defects in the telomerase enzyme. One example is Dyskeratosis Congenita (DKC), a rare genetic disease associated with dramatically shortened telomeres. DKC mutations may be inherited in X-linked recessive, autosomal dominant and autosomal recessive forms. The autosomal dominant form of this disease is caused by mutations in genes encoding telomerase components including the RNA component of telomerase, or in genes that encode proteins associated with telomerase. Patients with this form of DKC accumulate much less telomerase RNA but remain healthy until young adulthood. Mortality in these patients is the result of progressive bone marrow failure, although there are accompanying defects in skin, hair, nails, epithelia and lung tissue. From these symptoms, it seems probable that the cells directly affected in DKC are stem cells in tissues with a high cell turnover. It should be noted that the clinical presentation of DKC is not that of premature aging syndromes (progerias), which include atherosclerosis and dementia (See Figure 3). Surprisingly, in light of the requirement for stable telomeres in cancer (discussed below), DKC patients show an elevated risk of leukemia and certain other cancers. It may be that telomere instability in these patients predisposes to telomere fusions, with subsequent chromosome breakage and rearrangements leading to oncogenic transformation.
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