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Shelterin

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Shelterin (also called telosome) 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 (2-15 kilobases in humans) along with the 3'-AATCCC-5' (C-strand) complement, ending with a 50-400 nucleotide 3' (G-strand) overhang.[1][2] 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).[1][3]

The absence of shelterin causes telomere uncapping and thereby activates damage-signaling pathways that may lead to non-homologous end joining (NHEJ), homology directed repair (HDR),[4] end-to-end fusions,[5] genomic instability,[5] senescence, or apoptosis.[6]

Subunits

Shelterin coordinates the T-loop formation of telomeres

Shelterin has six subunits: TRF1, TRF2, POT1, RAP1, TIN2, and TPP1.[7] They can operate in smaller subsets to regulate the length of or to protect telomeres.

  • TRF1 (Telomere Repeat binding Factor 1): TRF1 is a homodimeric protein[1] that binds to the double-stranded TTAGGG region of the telomere. TRF1 along with TRF2 normally prevents telomerase from adding more telomere units to telomeres.[8] But when telomere lengthening is required, TRF1 recruits helicases[9] and interacts with tankyrases[10] to facilitate the process. TRF1 is highly expressed in stem cells, and is essential for generation of induced pluripotent stem cells.[11] TRF1 is upregulated in the brain cancer glioblastoma multiforme (GBM) in humans and mice, because of stem-cell quality of the cancer.[12] Genetic ablation and chemical inhibition of TRF1 in mouse models of the brain cancer glioblastoma, and chemical inhibition of cultured human GBM cells inhibited tumor growth.[12] TRF1 levels decrease with aging in humans and in mice.[13] Increasing TRF1 in mice by gene therapy (AAV9 delivery) improved memory and other measures of health span.[13] Conversely, inhibition of the PI3K/AKT pathway decreases TRF1, resulting in telomere-induced DNA damage.[14] TRF1 may recruit PINX1 to inhibit telomere elongation by telomerase.[6]
  • TRF2 (Telomere Repeat binding Factor 2) TRF2 is structurally related to TRF1, and helps to form T-loops.[5] TRF2 is a homodimeric protein[1] that binds to the double-stranded TTAGGG region of the telomere and prevents the recognition of double-strand DNA breaks.[15] Overexpression of TRF2 leads to telomere shortening.[5] Loss of TRF2 which leads to loss of the T-loop can activate p53 or ATM-mediated apoptosis.[16]
  • Both TRF1 and TRF2 recruit the other four subunits to the telomere.[17] Both TRF1 and TRF2 participate in telomere replication as well as in the prevention of replication fork stalling.[17] Exercise has been shown to upregulate both TRF1 and TRF2 in leukocytes as well as endothelial cells, thereby protecting against apoptosis.[18]
  • RAP1 (Repressor / Activator Protein 1): RAP1 is a stabilizing protein associated with TRF2.[19] RAP1 inhibits DNA repair.[20]
  • POT1 (Protection of Telomere 1): POT1 contains OB-folds (oligonucleotide/oligosaccharide binding) that bind POT1 to single-stranded DNA,[21] which increase its affinity for single-stranded TTAGGG region of telomeric DNA. POT1 helps form the telomere-stabilizing D-loop.[10] POT1 prevents the degradation of this single stranded DNA by nucleases and shelters the 3' G-overhang.[7] POT1 suppresses ATR-mediated DNA repair.[5] Humans only have a single POT1, whereas mice have POT1a and POT1b.[22] POT1a inhibits DNA damage repair at the telomere, whereas POT1b regulates the length of telomeric single-stranded DNA.[10]
  • TPP1 (ACD (gene)): TPP1 is a protein associated with POT1. The loss of TPP1 leads to impaired POT1 function.[6] When telomeres are to be lengthened, TPP1 is a central factor in recruiting telomerase to telomeres.[23] TPP1 promotes telomerase processivity in the presence of POT1.[5] But interaction with the CST Complex limits excessive telomere elongation by telomerase.[5] The gene which encodes for TPP1 (ACD) is distinct from the unrelated TPP1 gene on chromosome 11, which encodes tripeptidyl-peptidase I.[24]
  • TIN2 (TRF1- and TRF2-Interacting Nuclear Protein 2) TIN2 is a stabilizing protein that binds to the TRF1, TRF2, and the TPP1-POT1 complex.[25] thereby bridging units attached to double-stranded DNA and units attached to single-stranded DNA.[6]

Repression of DNA repair mechanisms

There are two main DNA-damage-signaling pathways that shelterin represses: the ATR kinase pathway, blocked by POT1, and the ATM kinase pathway, blocked by TRF2.[1] In the ATR kinase pathway, ATR and ATRIP sense the presence of single-stranded DNA and induce a phosphorylation cascade that leads to cell cycle arrest. To prevent this signal, POT1 "shelters" the single-stranded region of telomeric DNA. The ATM kinase pathway, which starts from ATM and other proteins sensing double strand breaks, similarly ends with cell cycle arrest. TRF2 may also hide the ends of telomeres, just as POT1 hides the single-stranded regions. Another theory proposes the blocking of the signal downstream. This will lead to a dynamic instability of the cells over time.

The structure of the t-loop may prevent NHEJ.[1] For NHEJ to occur, the Ku heterodimer must be able to bind to the ends of the chromosome. Another theory offers the mechanism proposed earlier: TRF2 hides the ends of telomeres.[6]

Species differences

At least four factors contribute to telomere maintenance in most eukaryotes: telomerase, shelterin, TERRA and the CST Complex.[26] Fission yeast (Schizosaccharomyces pombe) has a shelterin complex for protection and maintenance of telomeres, but in budding yeast (Saccharomyces cerevisiae) this function is performed by the CST Complex.[27] For fission yeast, Rap1 and Pot1 are conserved, but Tpz1 is an ortholog of TPP1 and Taz1 is an ortholog of TRF1 and TRF2.[28]

Plants contain a variety of telomere-protecting proteins which can resemble either shelterin or the CST Complex.[29]

The fruit fly Drosophila melanogaster lacks both shelterin and telomerase, but instead uses retrotransposons to maintain telomeres.[30]

Non-telomeric functions of shelterin proteins

TIN2 can localize to mitochondria where it promotes glycolysis.[31] TIN2 loss in human cancer cells has resulted in reduced glycolysis and increased oxidative phosphorylation.[5]

RAP1 regulates transcription and affects NF-κB signaling.[9]

See also

References

  1. ^ a b c d e f de Lange, Titia (2010). "How Shelterin Solves the Telomere End-Protection Problem" (PDF). Cold Spring Harbor Symposia on Quantitative Biology. 75: 167–77. doi:10.1101/sqb.2010.75.017. PMID 21209389.
  2. ^ Červenák F, Juríková K, Nosek J, Tomáška L (2017). "Double-stranded telomeric DNA binding proteins: Diversity matters". Cell Cycle. 16 (17): 1568–1577. doi:10.1080/15384101.2017.1356511. PMC 5587031. PMID 28749196.
  3. ^ Greider, Carol (1999). "Telomeres do D-loop-T-loop". Cell. 97 (4): 419–422. doi:10.1016/S0092-8674(00)80750-3. PMID 10338204.
  4. ^ Rodriguez, Raphaël; Müller, Sebastian; Yeoman, Justin A.; Trentesaux, Chantal; Riou, Jean-Françios; Balasubramanian, Shankar (2008). "A Novel Small Molecule That Alters Shelterin Integrity and Triggers a DNA-Damage Response at Telomeres". Journal of the American Chemical Society. 130 (47): 15758–59. doi:10.1021/ja805615w. PMC 2746963. PMID 18975896.
  5. ^ a b c d e f g h Jones M, Bisht K, Savage SA, Nandakumar J, Keegan CE, Maillard I (2016). "The shelterin complex and hematopoiesis". Journal of Clinical Investigation. 126 (3): 1621–1629. doi:10.1172/JCI84547. PMC 4855927. PMID 27135879.
  6. ^ a b c d e Palm W, de Lange T (2008). "How Shelterin Protects Mammalian Telomeres". Annual Reviews. 42: 301–34. doi:10.1146/annurev.genet.41.110306.130350. PMID 18680434.
  7. ^ a b Xin, Huawei; Liu, Dan; Songyang, Zhou (2008). "The telomere/shelterin complex and its functions". Genome Biology. 9 (9): 232. doi:10.1186/gb-2008-9-9-232. PMC 2592706. PMID 18828880.{{cite journal}}: CS1 maint: unflagged free DOI (link)
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  15. ^ Choi, Kyung H.; Farrell, Amy S.; Lakamp, Amanda S.; Ouellette, Michel M. (2011). "Characterization of the DNA binding specificity of Shelterin complexes". Nucleic Acids Research. 39 (21): 9206–23. doi:10.1093/nar/gkr665. PMC 3241663. PMID 21852327.
  16. ^ Dey A, Chakrabarti K (2018). "Current Perspectives of Telomerase Structure and Function in Eukaryotes with Emerging Views on Telomerase in Human Parasites". International Journal of Molecular Sciences. 19 (2): E333. doi:10.3390/ijms19020333. PMC 5855555. PMID 29364142.{{cite journal}}: CS1 maint: unflagged free DOI (link)
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  18. ^ Werner C, Fürster T, Widmann T, Pöss J, Roggia C, Hanhoun M, Scharhag J, Büchner N, Meyer T, Kindermann W, Haendeler J, Böhm M, Laufs U (2009). "Physical exercise prevents cellular senescence in circulating leukocytes and in the vessel wall". Circulation. 120 (24): 2438–2437. doi:10.1161/CIRCULATIONAHA.109.861005. PMID 19948976.
  19. ^ Nandakumar J1, Cech TR (2013). "Finding the end: recruitment of telomerase to telomeres". Nature Reviews Molecular Cell Biology. 14 (2): 69–82. doi:10.1038/nrm3505. PMC 3805138. PMID 23299958.{{cite journal}}: CS1 maint: numeric names: authors list (link)
  20. ^ Martínez P, Blasco MA (2018). "Heart-Breaking Telomeres". Circulation Research. 123 (7): 787–802. doi:10.1161/CIRCRESAHA.118.312202. PMID 30355079.
  21. ^ Flynn RL, Zou L (2010). "Oligonucleotide/oligosaccharide-binding fold proteins: a growing family of genome guardians". Critical Reviews in Biochemistry and Molecular Biology. 45 (4): 266–275. doi:10.3109/10409238.2010.488216. PMC 2906097. PMID 20515430.
  22. ^ Martínez P1, Blasco MA (2010). "Role of shelterin in cancer and aging". Aging Cell. 9 (5): 653–666. doi:10.1111/j.1474-9726.2010.00596.x. PMID 20569239.{{cite journal}}: CS1 maint: numeric names: authors list (link)
  23. ^ Abreu E, Aritonovska E, Reichenbach P, Cristofari G, Culp B, Terns RM, Lingner J, Terns MP (June 2010). "TIN2-tethered TPP1 recruits human telomerase to telomeres in vivo". Mol. Cell. Biol. 30 (12): 2971–82. doi:10.1128/MCB.00240-10. PMC 2876666. PMID 20404094.
  24. ^ "ACD ACD, shelterin complex subunit and telomerase recruitment factor [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2017-02-03.
  25. ^ Takai, Kaori K.; Hooper, Sarah; Blackwood, Stephanie; Gandhi, Rita; de Lange, Titia (2010). "In Vivo Stoichiometry of Shelterin Components". Journal of Biological Chemistry. 285 (2): 1457–67. doi:10.1074/jbc.M109.038026. PMC 2801271. PMID 19864690.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  26. ^ Giraud-Panis MJ, Teixeira MT, Géli V, Gilson E (2010). "CST meets shelterin to keep telomeres in check". Molecular Cell. 39 (5): 665–676. doi:10.1016/j.molcel.2010.08.024. PMID 20832719.
  27. ^ Price CM, Boltz KA, Chaiken MF, Stewart JA, Beilstein MA, Shippen DE (2010). "Evolution of CST function in telomere maintenance". Cell Cycle. 9 (16): 3157–3165. doi:10.4161/cc.9.16.12547. PMC 3041159. PMID 20697207.
  28. ^ Miyagawa K, Low RS, Santosa V, Tsuji H, Moser BA, Fujisawa S, Harland JL, Raguimova ON, Go A, Ueno M, Matsuyama A, Yoshida M, Nakamura TM, Tanaka K (2014). "SUMOylation regulates telomere length by targeting the shelterin subunit Tpz1(Tpp1) to modulate shelterin-Stn1 interaction in fission yeast". PNAS. 111 (16): 5950–5955. doi:10.1073/pnas.1401359111. PMC 4000806. PMID 24711392.
  29. ^ Procházková Schrumpfová P, Schořová Š, Fajkus J (2016). "Telomere- and Telomerase-Associated Proteins and Their Functions in the Plant Cell". Frontiers in Plant Science. 7: 851. doi:10.3389/fpls.2016.00851. PMC 4924339. PMID 27446102.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  30. ^ Pardue ML, DeBaryshe PG (2011). "Retrotransposons that maintain chromosome ends". PNAS. 108 (51): 20317–20324. doi:10.1073/pnas.1100278108. PMC 3251079. PMID 21821789.
  31. ^ Chen LY, Zhang Y, Zhang Q, Li H, Luo Z, Fang H, Kim SH, Qin L, Yotnda P, Xu J, Tu BP, Bai Y, Songyang Z (2012). "Mitochondrial localization of telomeric protein TIN2 links telomere regulation to metabolic control". Molecular Cell. 47 (6): 839–850. doi:10.1016/j.molcel.2012.07.002. PMC 3462252. PMID 22885005.
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