Telomeres, Telomerase, Cellular Aging, and Immortality
Full description or abstract
Telomeres, which define the ends of chromosomes, consist of short, tandemly repeated DNA sequences loosely conserved in eukaryotes. Telomerase is a ribonucleoprotein complex ( we only show a few of the components in this illustration) which in vitro recognizes a single-stranded G-rich telomere primer and adds multiple telomeric repeats to its 3-prime end by using an RNA template. Telomerase may also have a role in de novo formation of telomeres. Telomerase has been identified in many cultured cell lines and actively dividing cell types. The active reverse transcriptase component has been identified in teh TERT protein. The presence of this factor determines the availability of the telomerase function. The TERT protein has a high turnover rate and its expression is regulated by factors that promote growth (c-MYC, v-k-ras, Bcl-2 and E6) and inhibiting factors (RB and p53) that promote cell death or that block cell division. It appears that the regulation of active telomerase has many levels and can be inhibited by TEP1 not releasing TERT or by TRF1 which binds the end repeats and prevents access to the chromosome ends. Additional modulation is due to phosphorlyation by PKC and AKT or dephophorylation by PP2A. Wilke et al found that a case of human alpha-thalassemia was caused by a truncation of chromosome 16 that had been healed by the addition of telomeric repeats (TTAGGG)n. Human telomeres consist of many kilobases of (TTAGGG)n together with various associated proteins. Small amounts of these terminal sequences are lost from the tips of the chromosomes during each S phase because of incomplete DNA replication, but de novo addition of TTAGGG repeats by the enzyme telomerase compensates for this loss. Many human cells progressively lose terminal bases with each cell division, a loss that correlates with the apparent absence of telomerase in these cells. There has been considerable interest in the possible relationship between human telomeres and cellular senescence and immortalization. This interest includes the question of a role in the malignant process and the question of the use of telomerase inhibitors as anti-tumor drugs.
