The telomerase reverse transcriptase: components and regulation

The idea that chromosomes have special terminal structures first arose as a consequence of experiments conducted by Muller, who found that treatment of Drosophila with X-rays rarely resulted in terminal deletions or inversions of the chromosomes (Muller 1938). Complementary experiments in maize by McClintock expanded upon the idea that telomeres, the physical ends of chromosomes, are required for chromosome stability, by contrasting the breakage-fusion-bridge cycle resulting from broken dicentric chromosomes with the stability of chromosomes with intact termini (McClintock 1941, 1942). With the dawn of molecular biology, telomeres in most eukaryotes are now known to be composed of short repeated G-rich sequences complexed with proteins to form a special heterochromatin-like structure. More recent experimental manipulation of chromosome termini and of the proteins that bind them have confirmed the early observations of Muller and McClintock, showing that a primary role of telomeres is to insulate the ends of chromosomes both from fusion with other ends and from nucleolytic digestion (Counter et al. 1992; Sandell and Zakian 1993; Garvik et al. 1995; van Steensel et al. 1998).

Not only do telomeres function as protective caps at the ends of chromosomes, but they also facilitate the complete replication of chromosomes. Conventional DNA replication machinery utilizes an RNA primer to initiate DNA synthesis, leading to the problem that extreme terminal sequences will not be represented on the 5′ end of one daughter DNA strand, after removal of a terminal RNA primer. Without a mechanism to replenish these sequences, chromosomes will inevitably shorten as they proceed through successive divisions and, at some point, the ends of chromosomes will be too short to continue to provide the capping function necessary for maintaining genomic stability. The solution to this end-replication problem that has been adopted by most organisms is to use a …