3 Telomerase Biochemistry and Biogenesis

Abstract

THE TELOMERASE ENZYME
Telomerase is a specialized DNA polymerase that adds telomere repeats onto chromosome ends. The maintenance of telomeres by telomerase is conserved in most eukaryotes, and the enzymatic reaction catalyzed by telomerase is conserved. Thus, the essential function of telomerase in maintenance of telomere length likely arose early in evolution and had a critical role in allowing the establishment of linear chromosomes in eukaryotes.

The telomerase enzyme is a ribonucleoprotein (RNP) that consists of two essential core components: a catalytic protein component, telomerase reverse transcriptase (TERT), and an essential RNA component, telomerase RNA (TR). As the name implies, the TERT protein has regions of homology with the catalytic motifs of reverse transcriptase (Lingner et al. 1997b; Nakamura et al. 1997). This makes sense since telomerase copies a small template region of the RNA component to synthesize telomere DNA repeats. In addition to the reverse transcriptase motifs, as described in detail below, additional conserved motifs in TERT have other specific roles. The RNA component contains a short region that is complementary to the telomeric repeat sequence (Greider and Blackburn 1989; Shippen-Lentz and Blackburn 1990). This template region is copied using conventional Watson–Crick base-pairing to specify the telomeric sequence. Altering the sequence of the template region alters the telomere repeats synthesized by telomerase (Shippen-Lentz and Blackburn 1990; Yu et al. 1990). Unlike the TERT component, the sequence of the TR is not conserved across species. As described below, most TRs have a core structural domain containing the template region...