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telomere extension (stilt has 3'overhang)

FIGURE 8-37 Extension of the 3' end of the telomere by telomerase solves the end replication problem Although telomerase only dircctly extends the 3' end of the telomere, by providing an additional template for lagging strand DNA synthesis, both ends of the chromosome are extended-

Chapter ll, these enzymes "reverse transcribe" RNA into DNA instead of the more conventional transcription of DNA into RNA.) The telomerase synthesizes DNA to the end of the RNA template but cannot continue to copy the RNA beyond that point. The RNA template disengages from the DNA product, re-anneals to the last three nucleotides of the telomere, and then repeats this process.

The characteristics of telomerase are in some ways distinct and in other ways similar to those of other DNA polymerases. The inclusion of an RNA component, the lack of a requirement for an exogenous template, and the ability to use an entirely ssDNA substrate sets telomerase apart from other DNA polymerases. In addition, telomerase must have the ability to displace its RNA template from the DNA product to allow repeated rounds of template-directed synthesis. Formally, this means that telomerase includes an RNA-DNA helicase activity. On the other hand, like all other DNA polymerases, telomerase requires a template to direct nucleotide addition, can only extend a 3' end of DNA, uses the same nucleotide precursors, and acts in a processive manner, adding many sequence repeats each time it binds to a DNA substrate.

Telomerase Solves the End Replication Problem by Extending the 3' End of the Chromosome

When telomerase acts on the 3' end of the telomere, it only extends this end of the chromosome. How is the 5' end extended? This is accomplished by the lagging strand DNA replication machinery (Figure 8-37). By providing an extended 3' end, telomerase provides additional template for the action of the lagging strand replication machinery which can then extend the 5' end of the DNA. It is important to note that there will still be an ssDNA region at the end of the chromosome. The action of telomerase and the lagging strand replication machinery, however, can ensure that the telomere is maintained at sufficient length to protect the end of the chromosome from becoming too short (and potentially deleting important genes).

Although extension of telomeres by telomerase could theoretically go on indefinitely, proteins bound to the double-stranded regions of the telomere carefully regulate telomere length. These proteins act as weak inhibitors of telomerase activity. When there are only a few copies of the telomere sequence repeat, few of these proteins will be bound to Ihe telomere and telomerase activity will be activated. As the telomere gets longer, these proteins will accumulate and inhibit the telomerase. The repetitive nature of the telomeric DNA sequence means that variations in the length of the telomere are readily tolerated by the cell. Whether a chromosome has 200 or 400 repeats of the telomeric repeat, it will be protected from recombination and degradation.

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