Telomere-binding protein

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Telomere-binding proteins (also known as TERF, TRBF, TRF) function to bind telomeric DNA in various species. In particular, telomere-binding protein refers to TTAGGG repeat binding factor-1 (TERF1) and TTAGGG repeat binding factor-2 (TERF2). [1] Telomere sequences in humans are composed of TTAGGG sequences which provide protection and replication of chromosome ends to prevent degradation. Telomere-binding proteins can generate a T-loop to protect chromosome ends. [2] TRFs are double-stranded proteins which are known to induce bending, looping, and pairing of DNA which aids in the formation of T-loops. They directly bind to TTAGGG repeat sequence in the DNA. [3] There are also subtelomeric regions present for regulation. However, in humans, there are six subunits forming a complex known as shelterin. [4]

Contents

Structure

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. [5] TIN2, RAP1, TPP1 are adaptor proteins influencing signalling complexes. [6]

Both TRFs are separate homodimer proteins, similar to the Myb helix-turn-helix motif with DNA binding folds at the C-terminus. [7] There are highly conserved regions located in the centre with relation to the formation of homodimers. [8] 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. [7]

Function

The complex recognizes the TTAGGG telomeric sequences, indicating the end of a chromosome. [5] Telomere-binding proteins function to generate a T-loop, which is a specialized loop structure to cap the telomeric ends. Telomerase activity is regulated by protection of telomeres 1 (POT1). [9] 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. [5] [6] This is due to the 3’ overhang, which gradually shortens over time. A process known as uncapping occurs, in which the shelterin complex dissociates from the telomere when shrunk to a critical length. [6]

TERF1

TERF1 is present during all stages of the cell cycle, acting as a negative regulator in tandem with TERF2 while in contrast to telomerase. [8] Its main function seems to be observed in controlling the telomere lengths via inhibition of telomerase. Removal of TERF1 will therefore lead to an increase in telomere length. [8] TERF1 may reduce the accessibility of telomerase towards the end of the DNA length, which results in its inhibition. There may be potential post-translation modifications of TERF1 by adding ribose to induce regulation of telomerase. After the lengthening of the telomere, TERF1 reassembles to form an inaccessible T-loop structure. [10]

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. [7] TERF1 also serves to prevent problematic secondary structures from hindering progression by interacting with helicase for unobstructed unwinding. [4]

TERF2

TERF2 is a homolog to TERF1, exhibiting many functional and biochemical similarities. TERF2, like TERF1 has some relation to the Myb DNA binding motif. It serves as a secondary negative regulator, as overexpression of TERF2 produces a shortened telomere. [8] TERF2 may also conceal the ends of the telomere in order to prevent detection from degradation. [5] There is more conservation across species in TERF2 possibly due to higher risk of senescence when mutated. [11]

TERF2 binds directly to the DNA sequence, forming a T-loop structure. [12] Therefore, TERF2 plays a role in inducing loop formation by folding the 3’ TTAGGG sequence back into the duplex sequence. [8] 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. [12] Under regular cell conditions, TERF2 is known to suppress the ATM pathway, however, the mechanisms of which, are currently unclear. [4]

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. [4]

TERF2 requires stabilization for proper functioning through the interaction of TERF1 and TIN2. This suggests that a deficiency in either of the three former proteins will lead to a dysfunctional cell. [12] Despite being a negative regulator of telomerase, there are currently no known effects of TRFs on expression of telomerase. [8]

Damage response factors

When TERF2 is absent or non-functioning, ATM kinase is activated at chromosome ends to trigger a DNA damage response, similar to a response to a double-stranded break. This will then recruit damage response factors such as H2AFX and 53BP1 when telomeres are shortened and deprotected. [4] [12] Upon activation of ATM kinase, p53 is triggered to induce cell cycle arrest and initiate apoptosis. As well, damage detection will mediate non-homologous end joining (NHEJ), producing an end-to-end fusion of double-stranded breaks. However, it is not yet known how telomeres can detect the presence of damage. [12]

NER pathway

TERF2 also has implications in the nucleotide excision repair (NER) pathway based on experiments on K5-Terf2 mice. [13] It is suggested that individuals with critically short telomeres are more prone to skin cancer via UV-exposure. [5] 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. [13]

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. [13]

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. [10]

Related Research Articles

Telomere Nucleotide sequences

A telomere is a region of repetitive nucleotide sequences associated with specialized proteins at the ends of linear chromosomes. Although there are different architectures, telomeres, in a broad sense, are a widespread genetic feature most commonly found in eukaryotes. In most, if not all species possessing them, they protect the terminal regions of chromosomal DNA from progressive degradation and ensure the integrity of linear chromosomes by preventing DNA repair systems from mistaking the very ends of the DNA strand for a double strand break.

Telomerase Telomere-restoring protein active in the most rapidly dividing cells

Telomerase, also called terminal transferase, is a ribonucleoprotein that adds a species-dependent telomere repeat sequence to the 3' end of telomeres. A telomere is a region of repetitive sequences at each end of the chromosomes of most eukaryotes. Telomeres protect the end of the chromosome from DNA damage or from fusion with neighbouring chromosomes. The fruit fly Drosophila melanogaster lacks telomerase, but instead uses retrotransposons to maintain telomeres.

Subtelomeres are segments of DNA between telomeric caps and chromatin.

G-quadruplex Structure in molecular biology

In molecular biology, G-quadruplex secondary structures (G4) are formed in nucleic acids by sequences that are rich in guanine. They are helical in shape and contain guanine tetrads that can form from one, two or four strands. The unimolecular forms often occur naturally near the ends of the chromosomes, better known as the telomeric regions, and in transcriptional regulatory regions of multiple genes, both in microbes and across vertebrates including oncogenes in humans. Four guanine bases can associate through Hoogsteen hydrogen bonding to form a square planar structure called a guanine tetrad, and two or more guanine tetrads can stack on top of each other to form a G-quadruplex.

Telomeric repeat-binding factor 2 Protein

Telomeric repeat-binding factor 2 is a protein that is present at telomeres throughout the cell cycle. It is also known as TERF2, TRF2, and TRBF2, and is encoded in humans by the TERF2 gene. It is a component of the shelterin nucleoprotein complex and a second negative regulator of telomere length, playing a key role in the protective activity of telomeres. It was first reported in 1997 in the lab of Titia de Lange, where a DNA sequence similar, but not identical, to TERF1 was discovered, with respect to the Myb-domain. De Lange isolated the new Myb-containing protein sequence and called it TERF2.

Telomeric repeat-binding factor 1 Protein-coding gene in humans

Telomeric repeat-binding factor 1 is a protein that in humans is encoded by the TERF1 gene.

Telomerase RNA component NcRNA found in eukaryotes

Telomerase RNA component, also known as TR, TER or TERC, is an ncRNA found in eukaryotes that is a component of telomerase, the enzyme used to extend telomeres. TERC serves as a template for telomere replication by telomerase. Telomerase RNAs differ greatly in sequence and structure between vertebrates, ciliates and yeasts, but they share a 5' pseudoknot structure close to the template sequence. The vertebrate telomerase RNAs have a 3' H/ACA snoRNA-like domain.

POT1

Protection of telomeres protein 1 is a protein that in humans is encoded by the POT1 gene.

Tankyrase Enzyme

Tankyrase, also known as tankyrase 1, is an enzyme that in humans is encoded by the TNKS gene. It inhibits the binding of TERF1 to telomeric DNA. Tankyrase attracts substantial interest in cancer research through its interaction with AXIN1 and AXIN2, which are negative regulators of pro-oncogenic β-catenin signaling. Importantly, activity in the β-catenin destruction complex can be increased by tankyrase inhibitors and thus such inhibitors are a potential therapeutic option to reduce the growth of β-catenin-dependent cancers.

TINF2

TERF1-interacting nuclear factor 2 is a protein that in humans is encoded by the TINF2 gene. TINF2 is a component of the shelterin protein complex found at the end of telomeres.

ACD (gene)

Adrenocortical dysplasia protein homolog is a protein that in humans is encoded by the ACD gene.

TERF2IP

Telomeric repeat-binding factor 2-interacting protein 1 also known as repressor activator protein 1 (Rap1) is a protein that in humans is encoded by the TERF2IP gene.

PINX1

PIN2/TERF1-interacting telomerase inhibitor 1, also known as PINX1, is a human gene. PINX1 is also known as PIN2 interacting protein 1. PINX1 is a telomerase inhibitor and a possible tumor suppressor.

Tankyrase 2

Tankyrase-2 is an enzyme that in humans is encoded by the TNKS2 gene.

Alternative Lengthening of Telomeres is a telomerase-independent mechanism by which cancer cells avoid the degradation of telomeres.

Mega-telomere

A mega-telomere, is an extremely long telomere sequence that sits on the end of chromosomes and prevents the loss of genetic information during cell replication. Like regular telomeres, mega-telomeres are made of a repetitive sequence of DNA and associated proteins, and are located on the ends of chromosomes. However, mega-telomeres are substantially longer than regular telomeres, ranging in size from 50 kilobases to several megabases.

Shelterin is a protein complex known to protect telomeres in many eukaryotes from DNA repair mechanisms, as well as to regulate telomerase activity. In mammals and other vertebrates, telomeric DNA consists of repeating double-stranded 5'-TTAGGG-3' (G-strand) sequences along with the 3'-AATCCC-5' (C-strand) complement, ending with a 50-400 nucleotide 3' (G-strand) overhang. Much of the final double-stranded portion of the telomere forms a T-loop (Telomere-loop) that is invaded by the 3' (G-strand) overhang to form a small D-loop (Displacement-loop).

Titia de Lange Dutch geneticist

Titia de Lange is the Director of the Anderson Center for Cancer Research, the Leon Hess professor and the head of Laboratory Cell Biology and Genetics at Rockefeller University.

Telomeric repeat–containing RNA Long non-coding RNA transcribed from telomeres

Telomeric repeat–containing RNA (TERRA) is a long non-coding RNA transcribed from telomeres - repetitive nucleotide regions found on the ends of chromosomes that function to protect DNA from deterioration or fusion with neighboring chromosomes. TERRA has been shown to be ubiquitously expressed in almost all cell types containing linear chromosomes - including humans, mice, and yeasts. While the exact function of TERRA is still an active area of research, it is generally believed to play a role in regulating telomerase activity as well as maintaining the heterochromatic state at the ends of chromosomes. TERRA interaction with other associated telomeric proteins has also been shown to help regulate telomere integrity in a length-dependent manner.

Telomeres, the caps on the ends of eukaryotic chromosomes, play critical roles in cellular aging and cancer. An important facet to how telomeres function in these roles is their involvement in cell cycle regulation.

References

  1. ↑ Database, GeneCards Human Gene. "TERF2 Gene - GeneCards | TERF2 Protein | TERF2 Antibody". www.genecards.org. Retrieved 2017-11-30.
  2. ↑ Lee WK, Cho MH (June 2016). "Telomere-binding protein regulates the chromosome ends through the interaction with histone deacetylases in Arabidopsis thaliana". Nucleic Acids Research. 44 (10): 4610–24. doi:10.1093/nar/gkw067. PMC   4889915 . PMID   26857545.
  3. ↑ Ilicheva NV, Podgornaya OI, Voronin AP (2015-01-01). Donev R (ed.). Advances in Protein Chemistry and Structural Biology. Vol. 101. Academic Press. pp. 67–96. doi:10.1016/bs.apcsb.2015.06.009. ISBN   9780128033678. PMID   26572976.
  4. 1 2 3 4 5 Sfeir A (September 2012). "Telomeres at a glance". Journal of Cell Science. 125 (Pt 18): 4173–8. doi:10.1242/jcs.106831. PMC   6518153 . PMID   23135002.
  5. 1 2 3 4 5 de Lange T (September 2005). "Shelterin: the protein complex that shapes and safeguards human telomeres". Genes & Development. 19 (18): 2100–10. doi: 10.1101/gad.1346005 . PMID   16166375.
  6. 1 2 3 Cookson JC, Laughton CA (March 2009). "The levels of telomere-binding proteins in human tumours and therapeutic implications". European Journal of Cancer. 45 (4): 536–50. doi:10.1016/j.ejca.2008.11.014. PMID   19114299.
  7. 1 2 3 Bianchi A, Smith S, Chong L, Elias P, de Lange T (April 1997). "TERF1 is a dimer and bends telomeric DNA". The EMBO Journal. 16 (7): 1785–94. doi:10.1093/emboj/16.7.1785. PMC   1169781 . PMID   9130722.
  8. 1 2 3 4 5 6 Smogorzewska A, van Steensel B, Bianchi A, Oelmann S, Schaefer MR, Schnapp G, de Lange T (March 2000). "Control of human telomere length by TERF1 and TERF2". Molecular and Cellular Biology. 20 (5): 1659–68. doi:10.1128/mcb.20.5.1659-1668.2000. PMC   85349 . PMID   10669743.
  9. ↑ He Q, Zeng P, Tan JH, Ou TM, Gu LQ, Huang ZS, Li D (July 2014). "G-quadruplex-mediated regulation of telomere binding protein POT1 gene expression". Biochimica et Biophysica Acta (BBA) - General Subjects. 1840 (7): 2222–33. doi:10.1016/j.bbagen.2014.03.001. PMID   24631651.
  10. 1 2 Sainger RN, Telang SD, Shukla SN, Patel PS (February 2007). "Clinical significance of telomere length and associated proteins in oral cancer". Biomarker Insights. 2: 9–19. doi:10.1177/117727190700200030. PMC   2717828 . PMID   19662189.
  11. ↑ van Steensel B, Smogorzewska A, de Lange T (February 1998). "TERF2 protects human telomeres from end-to-end fusions". Cell. 92 (3): 401–13. doi: 10.1016/s0092-8674(00)80932-0 . PMID   9476899.
  12. 1 2 3 4 5 Celli GB, de Lange T (July 2005). "DNA processing is not required for ATM-mediated telomere damage response after TERF2 deletion". Nature Cell Biology. 7 (7): 712–8. doi:10.1038/ncb1275. PMID   15968270.
  13. 1 2 3 Muñoz P, Blanco R, Flores JM, Blasco MA (October 2005). "XPF nuclease-dependent telomere loss and increased DNA damage in mice overexpressing TERF2 result in premature aging and cancer". Nature Genetics. 37 (10): 1063–71. doi:10.1038/ng1633. PMID   16142233.
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