Open Access Open Access  Restricted Access Subscription or Fee Access

28 Telomere DNA Replication, Telomerase, and Human Disease

David C.F. Sealey, Lea Harrington, Virginia A. Zakian


Although chromosomes were first observed under the light microscope in the 1880s, it was not until the 1930s that the chromosome end, or telomere, was first appreciated to play a role in the protection from chromosome end-to-end fusions and instability (for review, see Blackburn 1992). In 1978, by chemical sequencing of telomeric DNA from the macronuclei of the ciliate Tetrahymena thermophila, the telomere was found to contain a few dozen repeats of the sequence TTGGGG (Black-burn and Gall 1978); these G-rich telomeric repeats are also conserved in other ciliates (Table 1) (for review, see Henderson 1995). By virtue of the ability of T. thermophila and Oxytricha fallax DNA termini to serve as substrates for “seeding” new telomeres on linear plasmids, telomeres from Saccharomyces cerevisiae were identified and found to comprise a similar G-rich sequence (Szostak and Blackburn 1982; Dani and Zakian 1983; Pluta et al. 1984; Shampay et al. 1984). The characteristic heterogeneous distribution of lengths for a given telomere in T.. thermophila and yeast indicated that telomere lengths vary considerably between chromosome ends within a population (Shampay et al. 1984; Shampay and Blackburn 1988).

Despite the limitations imposed by linear templates on DNA replication (termed the end replication problem; see below), telomeres do not shorten in several single-celled organisms upon continuous propagation. This observation, combined with the ability of telomeres to increase in size under certain conditions, led Greider and Blackburn to the eventual discovery of a terminal telomere transferase (telomerase) activity...

Full Text: