It was first reported in 1997 in the lab of Titia de Lange,[6] where a DNA sequence similar, but not identical, to TERF1 was discovered, with respect to the Myb-domain.

The basic domain sits at the N-terminal, and has two main functions: the prevention of t-loop excision by XRCC3, and the inhibition of SLX4.

TERF2 promotes t-loop formation by preferentially binding to a telomeric double-stranded DNA duplex containing a 3’ TTAGGG single-stranded overhang.

[12] Studies have demonstrated that deletion of TERF2 prevents t-loop formation, leading to excessive loss of telomeric DNA and early cell death.

However, because mutations in the TERF2 dimerization domain destabilize the protein, it has not been possible to test the contribution of TERF2 oligomerization on ATM repression directly.

Removal of TERF2 induces ATM-dependent apoptosis by localizing the active, phosphorylated form of ATM to unprotected chromosome ends.

As a result of removing this complex, several unwanted DNA damage response pathways are activated, including ATM kinase signaling, ATR kinase signaling, non-homologous end-joining (NHEJ), alt-NHEJ, C-NHEJ, 5' resection, and homology directed repair (HDR).

[15] These repair pathways (in the presence of P53 knockout and Cre) often contribute to the phenotype where chromosome ends are connected to each other in a very long chain, which can be visualized by a combination of a DAPI stain and fluorescence in situ hybridization (FISH) technique.

TERF2 has also been shown to interact with: Telomerase is an enzyme that works to create telomeric ends for DNA, and it is thought to play important roles in the development of cancer.

Shelterin works to protect telomeres against unsuitable activation of the DNA damage response pathway, as noted in the function section above.

TERF2 as part of the shelterin complex, has been known to block the ATM signaling pathways and prevent chromosome end fusion.

In cancer cells, TERF2 phosphorylation by extracellular signal-regulated kinase (ERK1/2) is a controlling factor in the major pro-oncogenic signaling pathways (RAS/RAF/MEK/ERK) that affect telomeric stability.

[24] One study used a dominant negative form of TERF2ΔBΔC, to inhibit TERF2, and found that it could induce a reversion malignant phenotype in human melanoma cells.