In human, telomere consists of thousands of repeats of six base pair motif (5’-TTAGGG-3’) ending in a G rich 3’ overhang 30-300 nt long, associated with a complex of six proteins named shelterin.
The structure prevents chromosome ends from being recognized as DNA double strand breaks and therefore being processed by the DNA repair machinery.
End replication problem is the inability of DNA polymerase to completely replicate the linear genomes, in which cells undergo telomere shortening at every replication round.
The loss of terminal DNA is counteracted by the activity of telomerase enzyme, which adds de novo telomeric repeats to the G rich 30- overhang.
Telomerase is active only in germ line and in stem cells, but not in somatic cells where telomeres shorten till they reach a critical length that activates a DNA damage response (DDR) leading to replicative senescence or to apoptosis.
Thus, limiting the number of cell division this constitutes an important barrier against cancer proliferation, because it reduces the risk of accumulating harmful mutations that could lead to malignant transformation.
Telomere erosion could result in high chromosomal instability and facilitates the generation of tumor promoting mutations, if cells escape p53 and Rb-dependent DNA damage checkpoints.
Telomeres are extremely dynamic structure and their organisation switch between a protected and a deprotected state throughout the cell cycle and cell differentiation, inorder to accomplish their multiple tasks.
During cell cycle, telomere structure has to change from a closed conformation concealing chromosome ends from repairing enzymes, to an open one in S phase inorder to allow controlled access to DNA replication factors.
In the telomerase negative cells, after reaching the critical short length of telomere, the uncap region will trigger the ATM/ATR signalling cascade, that eventually leads to a p53 dependent cell cycle arrest or apoptosis.
Capping of telomere requires the binding of specific proteins that recognize telomeric DNA and shields single stranded G overhangs by hiding them into specific structures.
T loops (Telomeric loop) are lasso like structures were the 3’ overhang folds back and invade the upstream telomeric region, generating a displacement loop (D-loop).
G – quadruplex are four stranded DNA structure, derived from folding of single stranded DNA containing runs of three to four consecutive guanines to form stacked tetrad of Gs, stabilized by Hoogsteen hydrogen bonding and cation coordination.
Both these structures need RTEL1 helicase inorder to be resolved and allow an efficient telomere replication.