Originally discovered as part of shelterin complex, telomeric repeat-binding factor 2 (TRF2, also called TERF2 or TRB2) is a ubiquitously expressed nuclear protein (55-60 kDa) involved in telomere homeostasis. TRF2 contains an N-terminal GAR domain, a central TRFH dimerization domain, and a C-terminal SAND/MYB-type DNA binding domain. Trf2 RNA has 10 exons and alternative splicing in rodents produces a truncated form, TRF2-S, which lacks the DNA binding domain and nuclear localization signal (NLS) (1).
Both TRF2 and TRF1 bind to telomeric double stranded 5'-TTAGGG-3' DNA repeats, then recruit RAP1, TIN2, TPP1, and POT1 for the assembly of the shelterin complex. The telomeric association of TRF2 is greatly increased in the S phase of the cell cycle (2). Loss of TRF2 leads to telomere shortening, the DNA damage response, chromosomal instability, and replicative senescence. Interestingly, the contribution of TRF2 to telomere shortening via a telomerase-independent mechanism has also been reported (3). In conjunction with the exonuclease, Apollo, TRF2 protects telomeres during replication and negatively regulates the accumulation of DNA topoisomerase (TOP1, TOP2A and TOP2B).
TRF2 has been implicated in cancer, shown to be a major oncogene in telomerase-deficient mice. A link to Werner syndrome, a premature aging disease caused by the loss of WRN, has been reported based on TRF2 recruitment of WRN for processing of telomeric DNA (4). TRF2 expression is increased during human embryonic stem cell differentiation and has been shown to interact with Repressor Element-1 Silencing Transcription Factor (REST), protecting it from proteasomal degradation (5).
1. Grammatikakis, I., Zhang, P., Mattson, M. P., & Gorospe, M. (2016). The long and the short of TRF2 in neurogenesis. Cell cycle (Georgetown, Tex.), 15(22), 3026-3032. PMID: 27565210
2. Li, F., Kim, H., Ji, Z., Zhang, T., Chen, B., Ge, Y., Hu, Y., Feng, X., Han, X., Xu, H., Zhang, Y., Yu, H., Liu, D., Ma, W., & Songyang, Z. (2018). The BUB3-BUB1 Complex Promotes Telomere DNA Replication. Molecular cell, 70(3), 395-407. PMID: 29727616
3. Ancelin, K., Brunori, M., Bauwens, S., Koering, C. E., Brun, C., Ricoul, M., Pommier, J. P., Sabatier, L., & Gilson, E. (2002). Targeting assay to study the cis functions of human telomeric proteins: evidence for inhibition of telomerase by TRF1 and for activation of telomere degradation by TRF2. Molecular and cellular biology, 22(10), 3474-3487. PMID: 11971978
4. Machwe A, Xiao L, & Orren DK. (2004) TRF2 recruits the Werner syndrome (WRN) exonuclease for processing of telomeric DNA. Oncogene. 23(1):149-56. PMID: 14712220.
5. Diotti, R., & Loayza, D. (2011). Shelterin complex and associated factors at human telomeres. Nucleus (Austin, Tex.), 2(2), 119-135. PMID: 21738835