Telomeres and Telomerase

The telomere is the protective end of a chromosome, composed of repeating six nucleotide guanine-rich sequences, for example, TTAGGG in humans.  Its length varies from organism to organism. In human chromosomes, there are approximately 1300 to 2500 telomere repeats present and around 8300 in mice. When the DNA replication machinery reaches the telomeres, it encounters a unique problem: the removal of the last primer at the 5’ end of the chromosome results in a 3’ overhang of single stranded telomeric DNA that cannot be copied because there is no complementary DNA to act as a template for the primer.  Due to this end-replication problem, the telomeres can become shortened with each cell division which eventually leads to the arrest of cell proliferation, also known as replicative senescence; however, this can be prevented by telomerase mediated synthesis of new telomere repeats.   Telomerase is an enzyme composed of both RNA with a template for telomere repeats and protein. It binds to the 3’ overhang of the telomere repeats. The protein component, a reverse transcriptase, extends the telomere DNA six nucleotides at a time, using the RNA, a cytosine-rich sequence complementary to the telomere repeats, as a template. Telomerase then translocates and repeats the process of the addition of nucleotides. DNA polymerase α, which contains its own primase subunit, can then add a primer and copy the extended parent DNA strand. After telomere extension, shelterin, a six-subunit protein, binds to the double-stranded piece of the telomere and the 3 prime overhang that remains after the removal of the primer. This complex then loops back and inserts itself in the upstream DNA resulting in a displacement loop, or D-loop, caused by the 3’ overhang binding to a complementary sequence in the telomere repeat. This insertion anchors the end of the telomere in place, forming a larger telomere loop, or T-loop. The binding of shelterin and the formation of the T-loop protects the chromosome from degradation, end-to-end fusion, and inappropriate activation of the DNA repair machinery.