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Telomere-binding protein

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Telomere-binding Protein Draft

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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 (TRF1) and TTAGGG repeat binding factor-2 (TRF2).[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]

Structure

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There are six subunits forming the telomere-binding protein complex known as shelterin. There include:

  • TRF1
  • TRF2
  • POT1
  • TIN2
  • RAP1
  • TPP1

Both TRF1 and TRF2 bind the telomeric repeat sequences in the duplex region of the genome in vivo. The DNA-binding proteins include TRF1, TRF2, 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 TRF2 contains a basic motif while TRF1 is acidic so they do not dimerize. There is a 120˚ angular bend in TRF1 when binding to the telomeric site.[7]

Cellular Function

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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 overtime. A process known as uncapping occurs, in which the shelterin complex dissociates from the telomere when shrunk to a critical length.[6]

TRF1

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TRF1 is present during all stages of the cell cycle, acting as a negative regulator in tandem with TRF2 while in contrast to telomerase.[8] Its main function seems to be observed in controlling the telomere lengths via inhibition of telomerase. Removal of TRF1 will therefore lead to an increase in telomere length.[8] TRF1 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 TRF1 by adding ribose to induce regulation of telomerase. After the lengthening of the telomere, TRF1 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. TRF1 binds near the N-terminus on a highly conserved domain to form a homodimer interaction. Since TRF1 bends the telomeric site, it may be a critical step in properly functioning telomeres to maintain its length.[7] TRF1 also serves to prevent problematic secondary structures from hindering progression by interacting with helicase for unobstructed unwinding.[4]

TRF2

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TRF2 is a homolog to TRF1, exhibiting many functional and biochemical similarities. TRF2, like TRF1 has some relation to the Myb DNA binding motif. It serves as a secondary negative regulator, as overexpression of TRF2 produces a shortened telomere.[8] TRF2 may also conceal the ends of the telomere in order to prevent detection from degradation.[5] There is more conservation across species in TRF2 possibly due to higher risk of senescence when mutated.[11]

TRF2 binds directly to the DNA sequence, forming a T-loop structure.[12] Therefore, TRF2 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 TRF2 alone may not necessarily lead to immediate shortening. Upon deletion of TRF2, there is co-localization with TRF1 with the association of DNA damage response factors.[12] Under regular cell conditions, TRF2 is known to suppress the ATM pathway, however, the mechanisms of which, are currently unclear.[4]

Interactions

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Shelterin Complex Subunits

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TRF1 and TRF2 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]

TRF2 requires stabilization for proper functioning through the interaction of TRF1 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

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When TRF2 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

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TRF2 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, TRF2, 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 TRF2 then initiates XPF activity leading to the excision of telomeric ends causing a reduction in length.[13]

Clinical Implications

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TRF2 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 TRF2 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 TRF2 causing genomic instability.[13]

[10]

Oral cancer also has a link to telomere-binding proteins, with TRF2 in particular. The overexpression of TRF2 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 TRF2 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

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  1. ^ Database, GeneCards Human Gene. "TERF2 Gene - GeneCards | TERF2 Protein | TERF2 Antibody". www.genecards.org. Retrieved 2017-11-30.
  2. ^ Lee, Won Kyung; Cho, Myeon Haeng (2016-06-02). "Telomere-binding protein regulates the chromosome ends through the interaction with histone deacetylases in Arabidopsis thaliana". Nucleic Acids Research. 44 (10): 4610–4624. doi:10.1093/nar/gkw067. ISSN 0305-1048.
  3. ^ Ilicheva, Nadya V.; Podgornaya, Olga I.; Voronin, Alex P. (2015-01-01). Donev, Rossen (ed.). Advances in Protein Chemistry and Structural Biology. Vol. 101. Academic Press. pp. 67–96.
  4. ^ a b c d e Sfeir, Agnel (2012-09-15). "Telomeres at a glance". J Cell Sci. 125 (18): 4173–4178. doi:10.1242/jcs.106831. ISSN 0021-9533. PMID 23135002.
  5. ^ a b c d e de Lange, Titia (2005-09-15). "Shelterin: the protein complex that shapes and safeguards human telomeres". Genes & Development. 19 (18): 2100–2110. doi:10.1101/gad.1346005. ISSN 0890-9369. PMID 16166375.
  6. ^ a b c Cookson, J. C.; Laughton, C. A. (2009-03-01). "The levels of telomere-binding proteins in human tumours and therapeutic implications". European Journal of Cancer. 45 (4): 536–550. doi:10.1016/j.ejca.2008.11.014.
  7. ^ a b c Bianchi, A.; Smith, S.; Chong, L.; Elias, P.; de Lange, T. (1997-04-01). "TRF1 is a dimer and bends telomeric DNA". The EMBO journal. 16 (7): 1785–1794. doi:10.1093/emboj/16.7.1785. ISSN 0261-4189. PMC 1169781. PMID 9130722.{{cite journal}}: CS1 maint: PMC format (link)
  8. ^ a b c d e f Smogorzewska, A.; van Steensel, B.; Bianchi, A.; Oelmann, S.; Schaefer, M. R.; Schnapp, G.; de Lange, T. (March 2000). "Control of human telomere length by TRF1 and TRF2". Molecular and Cellular Biology. 20 (5): 1659–1668. ISSN 0270-7306. PMID 10669743.
  9. ^ He, Qingqing; Zeng, Ping; Tan, Jia-Heng; Ou, Tian-Miao; Gu, Lian-Quan; Huang, Zhi-Shu; Li, Ding (July 2014). "G-quadruplex-mediated regulation of telomere binding protein POT1 gene expression". Biochimica Et Biophysica Acta. 1840 (7): 2222–2233. doi:10.1016/j.bbagen.2014.03.001. ISSN 0006-3002. PMID 24631651.
  10. ^ a b Sainger, Rachana N.; Telang, Shaila D.; Shukla, Shilin N.; Patel, Prabhudas S. (2007-02-14). "Clinical Significance of Telomere Length and Associated Proteins in Oral Cancer". Biomarker Insights. 2: 9–19. ISSN 1177-2719. PMC 2717828. PMID 19662189.{{cite journal}}: CS1 maint: PMC format (link)
  11. ^ van Steensel, B.; Smogorzewska, A.; de Lange, T. (1998-02-06). "TRF2 protects human telomeres from end-to-end fusions". Cell. 92 (3): 401–413. ISSN 0092-8674. PMID 9476899.
  12. ^ a b c d e Celli, Giulia B.; de Lange, Titia (July 2005). "DNA processing is not required for ATM-mediated telomere damage response after TRF2 deletion". Nature Cell Biology. 7 (7): 712–718. doi:10.1038/ncb1275. ISSN 1465-7392. PMID 15968270.
  13. ^ a b c Muñoz, Purificación; Blanco, Raquel; Flores, Juana M.; Blasco, María A. (October 2005). "XPF nuclease-dependent telomere loss and increased DNA damage in mice overexpressing TRF2 result in premature aging and cancer". Nature Genetics. 37 (10): 1063–1071. doi:10.1038/ng1633. ISSN 1061-4036. PMID 16142233.

[1][2][3][4][5]

Article Evaluation

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Genomic imprinting

This article is mostly thorough in providing a slightly more in-depth look into the topic of imprinting. My criticism towards this article is the initial definition of imprinting seems to be lacklustre and slightly misleading. The word imprinting is left loosely defined to be a secondary cause to another phenomenon rather than a solid definition in itself. This portrays the word genomic imprinting as a secondary topic or cause to the rest of what is discussed in the article. I would spend a sentence or two defining the origin of the word imprinting as it can give the reader an idea of the topic beforehand. When checking the "Talk" page, the definition of genomic imprinting remained contentious as well, which goes to show the vagueness of the term.

When talking about imprinted genes in mammals, the last sentence of the section regarding livestock is relevant; however, more clarity is needed to understand the concept of single-nucleotide polymorphisms in relation to the topic of genomic imprinting.

The article remains neutral throughout and serves as an unbiased encyclopedia. All the information, including the citations, are relevant and functional to the topic.

  1. ^ Ilicheva, Nadya V.; Podgornaya, Olga I.; Voronin, Alex P. (2015-01-01). Donev, Rossen (ed.). Advances in Protein Chemistry and Structural Biology. Vol. 101. Academic Press. pp. 67–96.
  2. ^ Lee, Won Kyung; Cho, Myeon Haeng (2016-06-02). "Telomere-binding protein regulates the chromosome ends through the interaction with histone deacetylases in Arabidopsis thaliana". Nucleic Acids Research. 44 (10): 4610–4624. doi:10.1093/nar/gkw067. ISSN 0305-1048. PMC 4889915. PMID 26857545.{{cite journal}}: CS1 maint: PMC format (link)
  3. ^ de Lange, Titia (2005-09-15). "Shelterin: the protein complex that shapes and safeguards human telomeres". Genes & Development. 19 (18): 2100–2110. doi:10.1101/gad.1346005. ISSN 0890-9369. PMID 16166375.
  4. ^ He, Qingqing; Zeng, Ping; Tan, Jia-Heng; Ou, Tian-Miao; Gu, Lian-Quan; Huang, Zhi-Shu; Li, Ding (July 2014). "G-quadruplex-mediated regulation of telomere binding protein POT1 gene expression". Biochimica Et Biophysica Acta. 1840 (7): 2222–2233. doi:10.1016/j.bbagen.2014.03.001. ISSN 0006-3002. PMID 24631651.
  5. ^ Cookson, J. C.; Laughton, C. A. (2009-03-01). "The levels of telomere-binding proteins in human tumours and therapeutic implications". European Journal of Cancer. 45 (4): 536–550. doi:10.1016/j.ejca.2008.11.014.
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