The ends of linear genomes are comprised of a unique and genetically stable structure termed telomere. Mammalian telomeres are composed of tandem repeats (TTAGGG)n that terminates in a 3’ single-stranded G-rich overhang that have a central role in sustaining a diverse array of telomeric functions. Indeed, the G-rich overhang that has approximately 30-500 nucleotides, folds back and invades the double-stranded telomeric helix, forming a lariat-like structure called telomeric loop or T-loop. The overhang pairs with the opposite strand, giving rise to a smaller displacement loop, the D-loop (Figure 1). This whole secondary structure is stabilized by the shelterin complex (Griffith, Comeau et al. 1999; di Fagagna, Reaper et al. 2003).The T-loop is also stabilized by the G-rich character of telomere 3’ single-stranded overhang. Indeed, the 3’ overhang takes on a secondary structure formed from the hydrogen bonding of guanine residues in tetrad formations, called G-quadruplex structure. This structure blocks telomerase physical access to telomeres, by preventing telomeric DNA linearization (Biffi, Tannahill et al. ; Sfeir ; Oganesian and Karlseder 2009).Mammalian telomeric DNA is assembled into evenly spaced nucleosomes that are enriched with repressive epigenetic marks that are characteristic of constitutive heterochromatin (Benetti, Garcia-Cao et al. 2007). The heterochromatic state of telomeres is important for proper telomere function, as it modulates telomere length and telomere ability to undergo homologous recombination (Schoeftner and Blasco).Telomeres solve two basic problems that are inherent to linear genomes. First, thanks to its specialized structure, they distinguish chromosome ends from DNA double-strand breaks, thereby preventing unwanted DNA-damage signaling and genome instability. Second, they prevent loss of essential genetic information (O'sullivan and Karlseder ; Gümüs-Akay and Tükün 2012). Telomere functions are mainly regulated by shelterin protein complex and telomerase enzyme.Shelterin complex Telomeric DNA is bound by the shelterin complex, composed of six proteins: TRF1 (telomeric repeat binding factor 1, also known as TERF1), TRF2 (telomeric repeat binding factor 2, also known as TERF2), RAP1 (TERF2 interacting protein, also known as TERF2IP), TIN2 (TRF1 interacting nuclear factor 2, also known as TINF2), TPP1 (adrenocortical dysplasia protein homolog, also known as ACD) and POT1 (protection of telomeres 1) (De Lange 2005). The exquisite specificity with which shelterin binds to the telomeric DNA is conferred by three of its components: TRF1 and TRF2 bind to the double stranded region of the DNA, whereas POT1 coats the single stranded overhang. The other three shelterin components bind to the telomeres through protein-protein interactions. RAP1 binds TRF2; TPP1 binds POT1; and TIN2 binds TRF1, TRF2 and TPP1 simultaneously (Sfeir ; Palm and de Lange 2008). Most shelterin components are essential to survival of mammalian cells, as its depletion either drives cells into cellular senescence or results in early embryonic lethality (Martinez and Blasco ; Patel, Vasan et al.). Together, shelterin complex protects chromosome ends from activating a DNA damage response, inhibits inappropriate repair mechanisms and maintains telomeric length and structure. However, each protein plays a unique role in telomere homeostasis.