The Key Role of Telomere Repeat Binding Factor 2 (TRF2) in Maintenance of Telomere Function

Telomeres are specialised nucleoprotein complexes at the end of long chromosomes, which consist of a multi-kilobase-long double-stranded repeating sequence of TTAGGG repeats, a single-stranded extension of the G-rich 3' strand, and proteins. This complex allows cells to differentiate broken DNA from native ends of chromosomes, which would stop native ends from communicating and triggering the DNA damage checkpoint cascade. Telomeres also contribute to cell fate – possibly because they do so many different things. They maintain chromosomal DNA ends that copy back to each other, they guard against the repair of DNA and activation of checkpoints, they regulate the meiotic spindle, they keep the ends of the chromosome in the nuclear cavity, and they modulate both long-term chromatin turnover and gene expression.

The telomere sequence in mammals binds to a complex of six telomere proteins called Shelterin that can resolve pressure on telomere DNA replication. Shelterin comprises of Telomere repeat binding factor 1 (TRF1), Telomere repeat binding factor 2 (TRF2), Protection of telomeres 1 (POT1), TRF1-interacting nuclear protein 2 (TIN2), TIN2 interacting protein (TPP1) and Repressor activator protein 1 (RAP1). TRF1 and TRF2 cleave to the telomeric double-stranded DNA, and TRF2 forms a heterodimer with RAP1. POT1 essentially associates with the telomere overhang and connects to TPP1 to control telomere length and end closure. TIN2 ties POT1-TPP1 to TRF1 and TRF2 into a large complex.

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Physiological Functions of Telomeres

Telomeres are an assembly of DNA sequences repeating and protein cousins lining the ends of eukaryotic chromosomes. These principal functions and side effects are:

Conserving Chromosomes

Telomeres might help shield the ends of chromosomes from degradation and fusion so that they aren't mistaken for broken during replication, and so no genetic material will be lost.

Stabilizing Genome

Telomeres keep the genome stable and prevent cancer and other genetic diseases that arise from genome instability.

Controlling Cell Death

Telomeres get shorter and shorter as cells divide. Cells age or die if their telomeres get too short. This is also a process responsible for controlling cell proliferation and ageing.

Assisting in Cell Aging and Mitosis

Telomere length closely corresponds to cell aging. We know that the telomeres themselves shorten in a crucial sign of ageing.

Effects on Stem Cell Activity

In stem cells, the length of the telomeres is directly associated with the self-renewal and stem-cell differentiation potential. Cells are really concerned with telomere maintenance for the health and survival of stem cells.

Telomeric Repeat Binding Factors 1 (TRF1) and 2 (TRF2)

Telomere repeat binding factors 1 (TRF1) and 2 (TRF2) The two molecules involved in this process are telomere repeat binding factor 1 (TRF1) and 2. TRF1 and TRF, which are essential for telomere maintenance. Two similar proteins (TRF1 and TRF2), together form a complex near the end of telomeres that guards telomeres from damage and degradation by DNA.

TRF1 and TRF2 attach directly to the double-stranded ends of telomeres. These two paralogs share domain structure and are identical in the TRF homology (TRFH) domain, the flexible hinge area, and the mob-type DNA binding area. TRF homology domain: these are amino acids that can homodimerize or homomultimerise multiple my domains into sequence-specific DNA binding. Strangely, the TRFH domain does not heterodimerize, so there are two complexes at telomeres - one based on TRF1 and one based on TRF2.

TRF2 Involved in Selection of Telomere Damage Repair Pathways

DNA repair pathways are selectively turned on during the cell cycle, and end-processing of DNA decides which DNA repair pathways to call on. C-NHEJ goes directly to broken ends, and the ssDNA from nuclease-mediated end resection fixes DSBs in Alt-NHEJ or HR. The genome could not repair DNA damage as effectively in telomeres as it could elsewhere because telomeres are heterochromatic, or because TRF2 inhibits NHEJ. Now TRF2 has been discovered to engage Nijmegen damage syndrome protein 1 (NBS1), cell cycle-dependently, in telomere damage repair pathway selection. TRF2 regulates telomere repair processes.

Fig. 1 Telomere damage repair pathways involved in TRF2 (Zong H., et al. 2020).

TRF2 and DNA Damage & Genome Stability

The eukaryotic DNA damage checkpoint is a key part of cellular genome stability. It can sense the cell DNA damage response (DDR). When DNA replication is disrupted or the shelterin complex is slowed down (telomere dysfunction), the cell ATM kinase signal can be sent to activate the ATM signal transduction system from telomere DNA damage (telomere DDR, ATM-dependent DDR). TRF2 guards against chromosome end being damaged and keeps the genome intact by inhibiting ATM-dependent signaling pathways such as its downstream mediators chk2 and P53. In contrast, the maintenance of genome stability also involves the repair of DSBs in DNA. These repair mechanisms are mainly non-homologous end joining (NHEJ) and homologous end recombination (HR). TRF2 mainly acts on classical non-homologous end joining (C-NHEJ). TRF2 binds to telomeric DNA and suppresses C-NHEJ activation (it also acts as an ATM antagonist). C-NHEJ chromosomal modifications are related to genomic instability during human tumor formation. The treatment with TRF2 that targets only C-NHEJ could thus be a novel form of tumor therapy.

Conclusion

The wrong way telomeres are replicated can result in instability of the chromosomes, abnormal cell division, cell death, or tumors. Shelterin protein complexes resolve replication stress in telomeres, suppressing abnormal DDR signals and DNA damage pathways, along with other proteins to keep the telomeres replicating normally. However, there is still much to be done in the coordination channels that connect telomere repair, preservation, replication, and telomerase activity. Meanwhile, more insight into how the telomere functions are maintained can give some clues and plans for telomere-associated diseases, including aging and cancer.

References

1. Zong H., et al. The role of telomere binding proteins in telomere replication and damage repair. Progress in Biochemistry and Biophysics. 2020, 48(12): 1448-1455.
2. Matsutani, N., et al. Expression of telomeric repeat binding factor 1 and 2 and TRF1-interacting nuclear protein 2 in human gastric carcinomas. International journal of oncology. 2001, 19(3): 507-512.