Telomerase inhibitors

Eukaryotic chromosomes are linear and have specialized ends called telomeres, which can be defined as regions of highly repetitive DNA at the end of a linear chromosome. The reason for the need for telomeres is that DNA polymerases extend DNA chains in the 5'-3' direction and require an RNA primer. For this reason, the 3'-5' chain, which is replicated in the 5'-3' direction (lead strand), can be replicated to the end, but the complementary chain (lagging strand) has to be replicated discontinuously starting from an RNA primer that is attached to the 5' end of each segment, resulting in a series of short fragments containing both RNA and DNA, called Okazaki fragments. The RNA fragments from the primer are subsequently degraded and replaced by DNA, leading to the fusion of the successive segments to form a single DNA strand. However, the RNA primer at the end of a complete lagging strand cannot be replaced because the required RNA primer would have no place to bind (Fig. 10.22). Therefore, when removed from the polymerase, the lagging strand of DNA would have an incomplete end, resulting in the loss of the final end and hence of genetic information.

Telomerase is a reverse transcriptase that contains an RNA molecule that generates repeating G-rich sequences (in humans, AGGGTT repeats with an average of 5-15 kb) and adds them to the 3' end of DNA, allowing the replication of the lagging strand to be completed (Fig. 10.23). Human telomerase is composed of at least two subunits, namely, telomerase RNA (TR or TERC) and telomerase

3/ The RNA primer r 3' | necessary for completing the lagging . chain would have no place to bind

y \ RNA primer

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