Figure 1. Model for the role of telomerase in the replication of linear chromosomal DNA termini in eukaryotes. (a) During the chromosomal DNA replication phase of the cell cycle (S phase), a DNA replication fork initiated from a replication origin within the chromosome moves toward the chromosomal DNA terminus. The helicase associated with the replication complex unwinds (curved arrow) the parental strands (marked A and B). (b) The transiently free single-stranded G-rich DNA 3¢ terminus of strand A is extended by telomerase (thick arrow). In vitro, telomerase requires a single-stranded 3¢ end of DNA as a primer, because the 3¢ end of the primer to be elongated is normally base-paired to the RNA template sequence. It is thought that telomerase acts during the S phase, perhaps using the opportunity afforded by the displacement of the complementary strand. Leading strand synthesis (lower rightward arrow) toward the chromosomal terminus copies all the way to the end of parental strand B, producing one full-length daughter DNA. (c) It has been suggested that an as yet unidentified DNA-processing activity produces the 3¢ overhang at the telomere by nucleolytic removal of the terminal portion of the C-rich telomeric DNA strand. The G-rich strand A, including its newly extended terminus, is copied by discontinuous lagging strand synthesis (zig-zag is RNA primer) by the primase-polymerase-mediated discontinuous synthesis typical of semiconservative DNA replication mechanisms. Removal of the most distal RNA primer leaves a 5¢ terminal gap, i.e. the protruding G-rich strand 3¢ overhang.

Figure 2. Polymerization of telomeric DNA by telomerase from the ciliated protozoan Tetrahymena. (a) The 3¢ nucleotides of the G-rich primer (red) base pair with the template region of the telomerase RNA, whose ribo A and ribo C nucleotide residues are shown. (b) The G-rich primer is elongated, copying the telomerase RNA template, making first round DNA extension products (lower case letters). (c) After copying the last (5¢ end) of the telomerase RNA template, the product can translocate and reposition for a second round of synthesis.

Figure 3. An example of the conserved core secondary structure of telomerase RNA of ciliated protozoa. The sequence of the templating domain nucleotides in Tetrahymena telomerase RNA is indicated (AACCCCAAC) and nucleotide numbers from the 5¢ end of the RNA are indicated. The conserved double-stranded RNA structures are shown as ladders marked I and IV, and the two helical components of the pseudoknot are ladders indicated as a and b. Adapted from Blackburn (1998).