Replication of telomeres and the regulation of telomerase

Abstract

Telomeres are the physical ends of eukaryotic chromosomes. They protect chromosome ends from DNA degradation, recombination, and DNA end fusions, and they are important for nuclear architecture. Telomeres provide a mechanism for their replication by semiconservative DNA replication and length maintenance by telomerase. Through telomerase repression and induced telomere shortening, telomeres provide the means to regulate cellular life span. In this review, we introduce the current knowledge on telomere composition and structure. We then discuss in depth the current understanding of how telomere components mediate their function during semiconservative DNA replication and how telomerase is regulated at the end of the chromosome. We focus our discussion on the telomeres from mammals and the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe.

Figure 1.

Telomeric proteins and telomerases at yeast and human telomeres. Only abundant telomere-binding proteins and telomerase components are indicated. Trf1 and Trf2 bind as homodimers to the double-stranded telomeric DNA repeats. Homologous proteins are shown in the same color.

Figure 2.

The end-replication problem and DNA end resection. The G-rich strand serves as a template for lagging-strand synthesis and the C-rich strand for leading-strand synthesis. The presumed blunt end intermediate at the leading-strand telomere is processed by 5′ end resection in order to recreate a 3′ overhang (right). Therefore, the leading-strand telomere shortens.

Figure 3.

Telomerase recruitment and telomere extension in S. cerevisiae. MRX recruits Tel1 to the shortest telomeres, which promotes telomerase recruitment through the interaction of Cdc13 with Est1. Tbf1 can also promote preferential extension of the shortest telomeres in tel1Δ cells. Cdk1 contributes to the cell-cycle-dependent recruitment of telomerase through phosphorylation of Cdc13. Telomerase extends telomeres in a nonprocessive manner in S. cerevisiae. Human telomerase, on the other hand, adds ∼60 nucleotides per telomere in a single binding and extension event (not shown; see text). Telomerase extension is terminated upon formation of the CST complex, which promotes recruitment of DNA Pol α-primase for fill-in synthesis.