Figure 2. Schematic representation of the telomeric structure in mammalian cells. (A) Human telomeres of the chromosomal-end are composed of TTAGGG DAN repeats with the single-stranded overhang of the telomere end. (B) Telomeres are folded into a larger t-loop structure. The 3′ overhang engages in strand invasion of the adjacent duplex telomeric repeat array, forming a D-loop.¹¹⁴ Telomere-binding proteins, including TRF1, TRF2, RAP1, TIN2, TPP1, and POT1, form the shelterin complex, which stabilizes the t-loop structure and protects the access of telomerase to telomeric DNA.¹¹⁵ TRF1 can bend, loop, and pair telomeric DNA in vitro and could potentially fold the telomere. The shelterin component TRF2 mediates t-loop formation in vitro by forming a complex with RAP1, which protects telomere DNA against DNA double-strand break repair mechanisms such as non-homologous end joining, and POT1 binds both to shelterin along the duplex telomeric DNA and to the single-stranded overhang DNA. Furthermore, tankylase 1 (TANK) associates with and poly ADP ribosylates TRF1, resulting in TRF1 release from telomeric DNA and increased telomerase access to the telomere. (C) The unfolded state of the t-loop allows telomerase to access and act on the single-stranded overhang DNA. The telomerase complex extends the telomere end by the addition of TTAGGG DNA repeats using TERC as a template for the telomere repeats.