Telomere-binding protein

There are six subunits forming the telomere-binding protein complex known as shelterin: TERF1, TERF2, POT1, TIN2, RAP1 and TPP1. Both TERF1 and TERF2 bind the telomeric repeat sequences in the duplex region of the genome in vivo. The DNA-binding proteins include TERF1, TERF2, and POT1, which have specific sequences, altering binding affinity or regulatory mechanisms. TIN2, RAP1, TPP1 are adaptor proteins influencing signalling complexes. Both TRFs are separate homodimer proteins, similar to the Myb helix-turn-helix motif with DNA binding folds at the C-terminus. There are highly conserved regions located in the centre with relation to the formation of homodimers. However, they differ in the N-terminus as TERF2 contains a basic motif while TERF1 is acidic so they do not dimerize. There is a 120˚ angular bend in TERF1 when binding to the telomeric site. == Function ==

The complex recognizes the TTAGGG telomeric sequences, indicating the end of a chromosome. They serve as a protective safeguard against premature degradation as the telomere ends are no longer hidden from damage detection. Telomere-binding proteins not present may cause the exposed telomeres to undergo a DNA repair response, having mistakenly identified the ends as a double-stranded break. It has homology to the Myb transcription factors as the protein-DNA complex requires both Myb repeats. TERF1 binds near the N-terminus on a highly conserved domain to form a homodimer interaction. Since TERF1 bends the telomeric site, it may be a critical step in properly functioning telomeres to maintain its length. TERF2 binds directly to the DNA sequence, forming a T-loop structure. Therefore, TERF2 plays a role in inducing loop formation by folding the 3’ TTAGGG sequence back into the duplex sequence. When removed, degradation of telomeric 3’ overhangs can be observed. However, this requires the work of excision repair exonuclease ERCC1/XPF so inhibition of TERF2 alone may not necessarily lead to immediate shortening. Upon deletion of TERF2, there is co-localization with TERF1 with the association of DNA damage response factors. Under regular cell conditions, TERF2 is known to suppress the ATM pathway, however, the mechanisms of which, are currently unclear. == Interactions ==

Shelterin complex subunits TERF1 and TERF2 have particular roles known to be associated with other subunits within the shelterin complex. They interact with TIN2 to recruit TPP1 binding by allowing TIN2 to form a bridge. As a result, a cascade of interactions follows by recruiting POT1 and RAP1 and the shelterin complex is complete to protect and regulate the telomeric ends. It is suggested that individuals with critically short telomeres are more prone to skin cancer via UV-exposure. As a result, TERF2, with roles in telomere-length controls, may affect UV-damage repair. For example, XPF nuclease, a component of NER, localizes to telomeres when the damage repair response is triggered. The presence of TERF2 then initiates XPF activity leading to the excision of telomeric ends causing a reduction in length. == Clinical implications ==

Skin tumours TERF2 may play a role in cancers as their expression has been shown to increase in human tumours. A study of tumours performed on mice induced overexpression of TERF2 in the skin. When exposed to light, notable observations showed hyperpigmentation and skin tumour similar to human syndrome xeroderma pigmentosum. They found significantly shortened telomeres with increased instability of the overall chromosome when analyzing cells. Telomere shortening was attributed to XPF, an excision repair nuclease, with link to TERF2 causing genomic instability. Oral cancer Oral cancer also has a link to telomere-binding proteins, with TERF2 in particular. The overexpression of TERF2 has been a notable similarity across patients with oral malignancies in humans. Similar to UV-damaged cells, there was an overall genomic instability leading to uncapping of the telomeric ends. The imbalance of TERF2 and telomerase have significant implications in cancer-inducing mechanisms. By targeting the telomere-binding proteins which serve to protect the ends, it may prove fruitful in future drug therapy. == References ==