Telomeric DNA comprises multiple hexameric TTAGGG repeat sequences found at the ends of chromosomes where it acts as protective caps to prevent the loss of coding genomic sequences. In normal somatic cells the telomere length is progressively reduced with each round of cell division because of incomplete DNA replication and DNA end processing. When telomere length reaches a critical point, cells stop dividing and undergoreplicative senescence. Mammalian telomeres are composed of tandem repeats ofthe 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 high erorder structure that mediate end cappingby masking telomeric DNA ends from recognition by the DNA repairsystem. Loss of telomeric cappingleads to chromosome end-to-end fusion and triggers cellcycle arrest and apoptosis that 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 byusing its integral RNA component as a template to add hexameric repeatsTTAGGG sequences to the mammalian telomeres to compensate for the loss of basepairsthat occurs after subsequent rounds of DNA replication. 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 calledTERC (Telomerase RNA Component; hTERC in humans), and a catalytic subunit called TERT (Telomerase Reverse Transcriptase; hTERT in humans). TERC, the RNA subunit act 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 telomerase first recognizing the 3’ overhanging telomeric sequence that exists at the chromosome ends. The telomerase RNA template sequence base pairs 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 repeats 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, holding the DNA end while the RNA slides down 6 bases to allow proper alignment and base pairing. Coordination between C-strand and G-strand synthesis is required for proper telomere length maintenance. The ability of telomerase to elongate telomeres is regulated by several other factors. In mammals, several other proteins are involved in telomere maintenance. These include the telomere-binding protein TRF1 (Telomeric Repeat Binding Factor 1)/Pin2, TRF2, TANK (TRF1-interacting, Ankyrin-related ADP-ribose polymerase, also known as Tankyrase), TIN2 (TRF1-Interacting Nuclear Factor2), and heterogeneous nuclear ribonucleoproteinssuch as HNRPA1 (Heterogeneous Nuclear Ribonucleoprotein A1), HNRPA2B1 (Heterogeneous Nuclear Ribonucleoprotein A2/B1) affect telomere maintenance. TRF1 is a negative regulator of telomere length, whereas TRF2 plays an essential role in protecting telomeric integrity. The TRF1 complex interacts with POT1 (Protection Of Telomeres-1; a single-stranded telomeric DNA-binding protein) and controls telomerase-mediated telomere elongation. TRF2 assists in the formation of the T-loop and helps to maintain the secondary structure of the telomere. TRF2 also interacts with several proteins, including the human RAP-1 (Repressor Activator Protein-1)/TERF2IP (Telomeric Repeat Binding Factor 2 Interacting Protein) and the MRE11 (Meiotic Recombination-11) complex, composed of MRE11, Rad50, and the NBS1 (Nijmegen Breakage Syndrome-1) protein, which is implicated in the cellular response to agents that damage DNA. In addition to the MRE11 complex, the Ku complex, involved in certain types of DNA double-stranded break repair, localizes to the telomere. Thus, the physiologic maintenance of the telomere requires complex interactions among these proteins, telomeric DNA, and other cellular factors.

Telomeres, Telomeric DNA, D-Loop, T-Loop,End-Capping, Telomerase, TERC, Telomerase RNA Component, hTERC, Human Telomerase RNA Component, TERT, Telomerase Reverse Transcriptase, hTERT, Human Telomerase Reverse Transcriptase, TRF1, Telomeric Repeat Binding Factor 1, PIN2,TRF2, TANK, TRF1-Interacting, Ankyrin-Related ADP-Ribose Polymerase, Tankyrase, TIN2, TRF1-Interacting Nuclear Factor2, POT1, Nuclear Ribonucleoproteins,HNRPA1, Heterogeneous Nuclear Ribonucleoprotein A1, HNRPA2B1, Heterogeneous Nuclear Ribonucleoprotein A2/B1, RAP-1, Repressor Activator Protein-1, ERF2IP, Telomeric Repeat Binding Factor-2, Interacting Protein MRE11, Meiotic Recombination-11, Rad50, NBS1, Nijmegen Breakage Syndrome-1 Protein, Ku Complex, Cancer, Replicative Senescence, Apoptosis, Fetal Tissues, Adult Germ Cells, Tumor Cells, Somatic Cells, Telomere Maintenance, Meiotic Chromosome Pairing, Meiotic Chromosome Segregation, Mitotic Chromosome Segregation, Cell Divisions, Aneuploidy, Cell Proliferation.