TRF2 (telomeric repeat-binding factor 2) is a homodimeric protein that binds the telomeric double-stranded 5'-TTAGGG-3' repeat for playing a critical role in the maintenance of telomeres as well as telomere's protection against end-to-end chromosomal fusion, and recruit a number of factors/enzymes required for telomere protection including shelterin complex/telosome (TERF1, TERF2, TINF2, TERF2IP/RAP1, ACD and POT1), TERF2IP/RAP1 and DCLRE1B/Apollo. Together with DCLRE1B/Apollo, TRF2 plays a key role in T-loopformation by generating 3' single-stranded overhang at the leading end telomeres and is required to control the amount of DNA topoisomerase (TOP1, TOP2A and TOP2B) needed for telomere replication during fork passage for preventing aberrant telomere topology. TRF2 recruits TERF2IP/RAP1 to telomeres, thereby participating into repressing homology-directed repair, which can impact telomeres length. Damaged telomeres have been shown to become associated with DNA-damage response factors such as 53BP1, MDC1, gamma-H2AX, ATM and the Mre11/Nbs1/Rad50 or MRN complex, and activate the ATM signaling, leading to cell cycle arrest mediated by the p53/p21 pathway. TRF2 interacts with PNUTS, MCPH1 and DEAD-box RNA helicase DDX39 also for regulating telomere length, telomeric DNA-damage response as well as genome integrity.