Replication of Telomeres—The End Game

Because DNA synthesis proceeds unidirectionally from 5´→3´ with respect to deoxyribose, by sequential addition of deoxynucleotides to the 3´ terminus of the deoxynucleotide added last, chain elongation can proceed to the terminus of the template strand oriented in the 3´ to 5´ direction. But how about synthesis of the terminus of the complementary strand ? Because synthesis of this discontinuous (lagging) strand occurs in the opposite direction by repeated synthesis of a primer, the terminus could not be replicated. This problem of end replication is eliminated in the circular genomes of bacteria and the small genomes of plasmids and viruses. However, in the case of linear eukaryotic chromosome, the problem is solved by a specialized mechanism of telomere replication. Telomeres are repeats of short G-rich sequences found at both ends of the chromosomes (Fig. 6). In the human genome, the telomere repeat unit is 5´ (T/A)m Gn 3´, where n>1 and 1< m < 4. Telomerase is a special DNA polymerase (reverse transcriptase) containing an oligoribonucleotide template 5´ Cn(A/T)m3´ (which is complementary to the telomere repeat sequence) as an integral part of the enzyme (Fig. 6). In the presence of other accessory proteins, telomerase utilizes its own template to generate the telomeric repeat unit and, by “slippage,” utilizes the same oligoribonucleotide template repeatedly to generate thousands of repeats of the same hexanucleotide unit sequence. Because the lagging strand terminal region does not require an external DNA template, the newly synthesized DNA is present in an extended single-stranded region. Telomeres provide a critical protective function to the chromosome by their unique structures and prevent their abnormal fusion.