Telomeres in Cell Function: Cancer and Ageing

Abstract

Telomeres, dynamic structures capping the ends of chromosomes, are composed of long arrays of repeated deoxyribonucleic acid (DNA) sequences accompanied by closely associated proteins. In most organisms, these repeats are maintained by the enzyme, telomerase. Telomeres were long thought to do no more than assure the physical integrity of chromosome ends. It is now recognized that telomere activity includes involvement with genomic replication, repair and maintenance machinery. Telomeres predate multicellular organisms, and their length regulation evolved differently in widely separated lineages; in humans, telomerase is inactivated in most somatic cells and, therefore, telomeres shorten with age. Telomeres play important roles in assuring genetic material is partitioned equally in cell division, in activating tumourā€suppressor genes in ageing tissue and in epigenetically regulating nearby subtelomeric genes for rapid response to the environment. With these involvements in fundamental cellular machinery, telomeres are more than bystanders in the cellular processes of ageing and cancer.

Key Concepts

  • Telomeres, which cap the ends of chromosomes, are composed of long arrays of repeated DNA sequences and closely associated proteins. Telomeres are thought to have evolved to protect faithful genome replication as cells acquired large genomes, cellular nuclei and multiple chromosomes.

  • Telomereā€associated proteins include some that are central to the repair of broken chromosomes and to the cell cycle checkpointing that prevents cells with nonviable broken chromosomes from propagating.

  • In most organisms, telomere repeats are maintained by the enzyme, telomerase, which replaces the few terminal nucleotides that are lost at each cycle of DNA replication, as well as nucleotides lost to enzymatic degradation. Lost sequences are replaced by copying from the enzyme's RNA component.

  • Telomere and telomerase activities are varied and important in many aspects of the control of cellular replication.

  • Telomeres prevent the cell from treating chromosome ends as broken chromosomes.

  • They help to ensure equal distribution of genetic material into each gamete at meiosis.

  • They are involved in regulating the expression of highly variable subtelomeric genes in response to environmental changes.

  • The full range of telomere and telomerase activities has not yet been explored but, given what we already know, these activities must be tightly controlled for the safety of the cell.

  • In organisms from yeast to humans the loss of telomerase activity leads to telomere shortening and eventually to replicative senescence.

  • Given their intimate involvement in cellular replication, telomeres and telomerase appear to have been frequently coopted in evolving controls for pathogenic genomic replication. These controls have evolved differently in different organisms, although all conserve the basic mechanism of telomere maintenance.

  • Telomerase must be active in certain cell types like germline cells, to ensure that gametes carry complete telomeres, and in epithelial and blood cells that turn over very rapidly.

  • In humans, telomerase activity is turned off in many somatic cells, although this restricts the number of cell divisions of these cells and contributes to senescence. This regulation is believed to have evolved as a protection against telomerase going wild and leading to cancer.

  • In yeast telomerase is normally active in all cells.

Keywords: cancer and ageing; chromosomes; DNA replication; telomeres; telomerase

Figure 1.

Telomere repeats differ between species but most are very similar. Typical sequences added by telomerase are shown. All are (G+T)‐rich. The most notable difference between the telomere DNA of multicellular organisms (human, tomato and silk moth) and unicellular organisms (the slime mold, Physarum, and budding yeast) is the length of the repeat arrays, which are thousands of base pairs long in multicellular organisms and only a few hundreds of base pairs in unicellular organisms.

Figure 2.

Building blocks of chromosomal DNA. DNA, deoxyribonucleic acid, is a molecule whose building blocks are four nucleotides. The DNA nucleotides (mononucleotides) are, themselves, formed by the chemical linking of one of the four ‘bases’ (cytosine, thymine, adenine or guanine) to a modified 5‐carbon sugar, β‐d‐2‐deoxyribose (indicated by aqua pentagons with the carbon positions numbered in red). The sugar is modified by the replacement of a hydroxyl (OH) group on the so‐called 5′ carbon (shown at the upper left end of the sugar molecule) by a phosphate (PO42−) group. These mononucleotides are linked to form unidirectional, polarized molecules of single‐stranded DNA. This linkage takes place when the OH on the 3′ carbon of the sugar moiety is replaced by a phosphodiester bond to the 5′ carbon on the next sugar of the linear molecule, as shown in the dinucleotide. The polymer grows by repeated linking of monomers to the 3′‐OH on the chain of mononucleotides. Nomenclature: Because strings of nucleotides are always attached with a 5′ carbon's phosphate group linked to its neighbour's 3′ carbon by displacing the 3′ hydroxyl group, it is common for biologists to refer to directionally sensitive processes as proceeding 5′→3′ along one or another strand.

Figure 3.

DNA polymerase cannot completely replicate the end of linear DNA. This diagram illustrates the replication of the end of linear DNA in the absence of a special mechanism for end replication. The final stages of replication of one end of the chromosome are shown. Replication has initiated at an internal origin, and, for simplicity, is drawn as proceeding only to the right (dotted lines on the left indicate that most of the chromosome is not shown). The replication machinery moves towards the end of the chromosome but polymerization proceeds 5′→3′ along each daughter strand. Note that base pairing makes paired strands antiparallel so that the 5′ end of a daughter strand lies next to its mother strand's 3′ end, and vice versa. Thus, one strand (the leading strand) can be synthesized 5′→3′ continuously, whereas the opposite strand (the lagging strand) must be synthesized backwards in short fragments as the machinery moves along the chromosome. Parental DNA strands are blue, new DNA is aqua. DNA polymerase can initiate polymerization only if provided with a 3′‐OH primer. The 3′‐OH is supplied by short (usually 8–12 base pairs) RNA fragments (pink). When synthesis is completed, the RNA is removed, leaving gaps, which are filled in by DNA polymerase, primed by the 3′‐OH of the DNA upstream of the gap. Because the final gap on the lagging strand has no upstream 3′‐OH, it cannot be filled and it will lack the last few nucleotides at its 5′ end. Similarly, at the other end of the chromosome (not shown), the other daughter strand will also lack a few nucleotides at its 5′ end.

Figure 4.

Telomerase compensates for DNA loss caused by under‐replication. This diagram illustrates schematically how telomerase compensates for loss of terminal nucleotides on linear DNA. Only one end of the chromosome is shown, although repeats are also added to the 3′ end of the other strand. The enzyme extends the 3′ end of the longer dark blue strand by copying DNA onto it from an RNA template that is part of the enzyme (reverse transcription). These repeats are shown as a light blue dashed line even though they are a continuous array. This array is replicated onto the aqua sister strand by DNA polymerase to make double‐stranded DNA. (The RNA primers, used by the DNA polymerase to complement the telomerase‐generated repeats, are shown in pink.) Although this replication will leave a short gap at the 5′ end of the aqua strand, this loss can be replaced at the next replication by reverse transcription of telomeraseRNA.

Figure 5.

Reverse transcription by telomerase and retrotransposons (relatives of retroviruses). This diagram compares the action of telomerase (at top of figure) with that of the reverse transcriptases of retrotransposons (at bottom of figure). The catalytic subunit of telomerase and an unknown number of accessory proteins (all protein components are represented by the yellow area) associates with the chromosome end and base pairs the 3′ end of the template segment of its RNA component (red) with the last few terminal nucleotides of the last repeat on the chromosome. The template segment shown here is from the first telomerase discovered, from the protozoan, Tetrahymena, and is depicted by the first letters of the RNA nucleotides it copies. The Tetrahymena template is 1 1/2 copies of the telomere repeat, the first three template nucleotides base pair with the outermost three nucleotides of the terminal DNA and align the template. Primed by the 3′‐OH on the end of the upper DNA strand, the enzyme copies one complete repeat from its template and then moves to realign with the new end of the strand and repeat its action. In contrast, most retrotransposable elements (retroviruses and retrotransposons) insert themselves into the interior of the chromosome. However, in fruit flies (Drosophila), three different retrotransposons can be reverse transcribed directly onto the ends of the chromosomes, where they form a unique telomere structure. The end replication process of the reverse transcriptases of these retrotransposable elements differ from telomerase most obviously by (1) reverse transcribing the entire length of their RNA component (several thousands of nucleotides) rather than a short defined segment and (2) not using base pairing to align their RNA template with the chromosome; they simply copy the template into DNA from a convenient 3′‐OH primer without alignment. As in the cartoon representing telomerase, the catalytic subunit of reverse transcriptase and associated proteins are yellow and the RNA template red.

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Further Reading

McEachern M (2008) Telomeres: Guardians of genomic integrity or double agents of evolution. In: Nosek J and Tomaska L (eds) Origin and Evolution of Telomeres, pp. 100–113. Austin, TX: Landes Bioscience. http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=eurekah.chapter73273

Pardue M‐L and DeBaryshe PG (2008) Drosophila telomeres: a variation on the telomerase theme. In: Nosek J and Tomaska L (eds) Origin and Evolution of Telomeres, pp. 27–44. Austin, TX: Landes Bioscience. http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=eurekah.chapter75481

Stewart SA and Weinberg RA (2006) Telomeres: Cancer to human aging. Annual Review of Cell and Developmental Biology 22: 531–557.

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Pardue, Mary‐Lou, and DeBaryshe, Gregory(Sep 2009) Telomeres in Cell Function: Cancer and Ageing. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001168.pub2]