Figure 5–33 Structure of a portion of telomerase. Telomerase is a large protein– RNA complex. The RNA (blue) contains a templating sequence for synthesizing new DNA telomere repeats. The synthesis reaction itself is carried out by the reverse transcriptase domain of the protein, shown in green. A reverse transcriptase is a special form of polymerase enzyme that uses an RNA template to make a DNA strand; telomerase is unique in carrying its own RNA template with it. Telomerase also has several additional protein domains (not shown) that are needed to assemble the enzyme at the ends of chromosomes. (Modified from J. Lingner and T.R. Cech, Curr. Opin. Genet. Dev. 8:226–232, 1998. With permission from Elsevier.)
Figure 5–34 Telomere replication. Shown here are the reactions that synthesize the repeating sequences that form the ends of the chromosomes (telomeres) of diverse eukaryotic organisms. The 3ʹ end of the parental DNA strand is extended by RNA-templated DNA synthesis; this allows the incomplete daughter DNA strand that is paired with it to be extended in its 5ʹ direction. This incomplete, lagging strand is presumed to be completed by DNA polymerase α, which carries a DNA primase as one of its subunits (Movie 5.6). The telomere sequence illustrated is that of the ciliate Tetrahymena, in which these reactions were first discovered.
Because the processes that grow and shrink each telomere sequence are only approximately balanced, a chromosome end contains a variable number of telomeric repeats. Not surprisingly, many cells have homeostatic mechanisms that maintain the number of these repeats within a limited range (Figure 5–36).
In most of the dividing somatic cells of humans, however, telomeres gradually shorten, and it has been proposed that this provides a counting mechanism that helps prevent the unlimited proliferation of wayward cells in adult tissues. In its simplest form, this idea holds that our somatic cells start off in the embryo with a full complement of telomeric repeats. These are then eroded to different extents in different cell types. Some stem cells, notably those in tissues that must be replenished at a high rate throughout life—bone marrow or gut lining, for example— retain full telomerase activity. However, in many other types of cells, the level of telomerase is turned down so that the enzyme cannot quite keep up with chromosome duplication. Such cells lose 100–200 nucleotides from each telomere every time they divide. After many cell generations, the descendant cells will inherit chromosomes that lack telomere function, and, as a result of this defect, activate a DNA-damage response causing them to withdraw permanently from the cell cycle and cease dividing—a process called replicative cell senescence (discussed in Chapter 17). In theory, such a mechanism could provide a safeguard against the uncontrolled cell proliferation of abnormal cells in somatic tissues, thereby helping to protect us from cancer.
fraction of chromosome ends
Figure 5–35 A t-loop at the end of a mammalian chromosome. (A) Electron micrograph of the DNA at the end of an interphase human chromosome. The chromosome was fixed, deproteinated, and artificially thickened before viewing. The loop seen here is approximately 15,000 nucleotide pairs in length. (B) Structure of a t-loop. The insertion of the single-strand 3ʹ end into the duplex repeats is carried out, and the structure maintained, by specialized proteins. (From J.D. Griffith et al., Cell 97:503–514, 1999. With permission from Elsevier.)