Telomere Extension by Telomerase

Telomeres are dynamic DNA-protein complexes that cap the ends of linear chromosomes, preventing detrimental chromosome rearrangements and defending against genomic instability and the associated risk of cancer. Telomeres shorten every time a cell divides because of incomplete DNA replication and DNA end processing. When telomere length reaches a critical point, cells stop dividing and undergo replicative senescence. Mammalian telomeres are composed of tandem repeats of the TTAGGG sequence and an array of associated proteins. Telomeres end in a 3' overhang, known as the G-strand overhang, which bends back on itself and anneals with the complementary sequences in the 5' end of the opposite strand. This displaces part of the 5' end in a D-loop and creates a telomere or T-loop, which is stabilized by a set of specialized proteins. T-loops facilitate the formation of a higher order structure that mediate end capping by masking telomeric DNA ends from recognition by the DNA repair system. Loss of telomeric capping leads to chromosome end-to-end fusion and triggers cell cycle arrest and apoptosis which contribute to the aging process. When they are not being replicated, telomeres are bound by a protein or protein complex whose function is to protect the telomere from degradation.Telomerase, also called telomere terminal transferase, prevents telomere shortening by using its integral RNA component as a template to add hexameric repeats (TTAGGG sequences) to mammalian telomeres. It is found in fetal tissues, adult germ cells and tumor cells and has a very low, almost undetectable activity in somatic cells. Telomerase has two essential components, an RNA molecule called TERC and a catalytic subunit called telomerase reverse transcriptase (TERT). TERC acts in concert to elongate telomeres by reading from the RNA template sequence carried by the RNA subunit and synthesizing a complementary DNA strand. The mechanism of telomerase synthesis involves the enzyme first recognizing the 3' overhanging telomeric sequence that exists at the chromosome ends. The telomerase RNA template sequence basepairs with the terminal TTAGGG repeat to initiate elongation of the 3' DNA end. The RNA template has only 11 bases that match the TTAGGG repeat sequence such that only one repeat of the sequence can be added in a single elongation. Synthesis terminates with the circularly permuted sequence GGTTAG. Telomerase can continue to synthesize telomeric repeats on the same DNA strand by unwinding the DNA from the DNA-RNA hybrid and holding the DNA end while the RNA slides down 6 bases to allow proper alignment and base pairing. The ability of telomerase to elongate telomeres is regulated by several other factors including TRF1/Pin2, Tankyrase and TIN2. TRF1 is a negative regulator of telomere length but it plays an essential role in protecting telomeric integrity.Beyond their role in replication and capping, telomeres participate in meiotic chromosome pairing, meiotic and mitotic chromosome segregation, and in the organization of the nucleus. Telomeres and telomerase are very important determinants of cell fate and cell life span. Telomere integrity is also essential for chromosome numerical and positional stability, and telomere shortening facilitates the evolution of cancer cells by promoting chromosome end-to-end fusions and the development of aneuploidy.