Telomere Shortening: Linkage Between Telomere Length and Limited Life Span

One profound implication of the specialized telomere structure and its synthesis is that in the absence of telomerase, the repeat length of telomeres could not be maintained. Telomerase is active in neonatal cells and also in some immortal tumor cells, but is barely detectable in diploid, terminally differentiated mammalian cells. Most such diploid cells can multiply in vitro in specialized culture medium, but have a limited life span. Loss of replicative capacity is associated with shortening of telomere repeat lengths. Furthermore, ectopic and stable expression of telomerase in human diploid cells by introduction of its gene confer an indefinite reproductive life on such cells. It is generally believed that cells will senesce if the telomere length is reduced belowa critical level after repeated replication of the genome.

FIGURE 6 A schematic description of the role of telomerase in the maintenance of telomeres at chromosome termini. The double lines with break represent one telomere terminus of a chromosome in which the 5´ terminal region of the lagging strand is unreplicated (as in Fig. 4), resulting in an overhanging 3´ terminal region. In order to avoid shortening of this telomere sequence during successive rounds of replication, DNA template-independent telomerase extends the 3´ overhang by adding the telomere repeat sequence TTGGGG as shown in (C). The template for the repeat is an RNA present in the telomerase complex. The extended 3´ single-strand region then allows de novo initiation and filling in of the 5´ strand (E). Finally, the 3´ overhang loops to anneal with an internal sequence mediated by the telomere repeat factor (TRF2) in order to protect the terminus from degradation by nonspecific nucleases (F).