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Shelterin Proteins and Cancer

  • Patel, Trupti NV (Department of Medical Biotechnology, Vellore Institute of Technology) ;
  • Vasan, Richa (Department of Medical Biotechnology, Vellore Institute of Technology) ;
  • Gupta, Divanshu (Department of Medical Biotechnology, Vellore Institute of Technology) ;
  • Patel, Jay (Department of Medical Biotechnology, Vellore Institute of Technology) ;
  • Trivedi, Manjari (Department of Medical Biotechnology, Vellore Institute of Technology)
  • Published : 2015.04.29

Abstract

The telomeric end structures of the DNA are known to contain tandem repeats of TTAGGG sequence bound with specialised protein complex called the "shelterin complex". It comprises six proteins, namely TRF1, TRF2, TIN2, POT1, TPP1 and RAP1. All of these assemble together to form a complex with double strand and single strand DNA repeats at the telomere. Such an association contributes to telomere stability and its protection from undesirable DNA damage control-specific responses. However, any alteration in the structure and function of any of these proteins may lead to undesirable DNA damage responses and thus cellular senescence and death. In our review, we throw light on how mutations in the proteins belonging to the shelterin complex may lead to various malfunctions and ultimately have a role in tumorigenesis and cancer progression.

Keywords

References

  1. Alessandro B, Susan S, Laura C, Peter E, Titia de L (1997). TRF1 is a dimer and bends telomeric DNA. EMBO J, 16, 1785-94. https://doi.org/10.1093/emboj/16.7.1785
  2. Bas VS, Titia de L (1997). Control of telomere length by the human telomeric protein TRF1. Nature, 385, 740-3. https://doi.org/10.1038/385740a0
  3. Bas VS, Agata S, Titia de L (1998). TRF2 protects human telomeres from end to end fusions. J cell, 32, 401-13.
  4. Baumann P, Cech TR (2001). Pot1, the putative telomere endbinding protein in fission yeast and humans. Science, 292, 1171-5. https://doi.org/10.1126/science.1060036
  5. Baumann P, Podell E, Cech TR (2002). Human Pot1 (protection of telomeres) protein: cytolocalization, gene structure, and alternative splicing. Mol Cell Biol, 22, 8079-87. https://doi.org/10.1128/MCB.22.22.8079-8087.2002
  6. Chen LY, Liu D, Songyang Z (2007). Telomere maintenance through spatial control of telomeric proteins. Mol Cell Biol, 27, 5898-909. https://doi.org/10.1128/MCB.00603-07
  7. Davoli T, Denchi EL, de Lange T (2010). Persistent telomere damage induces bypass of mitosis and tetraploidy. Cell, 141, 81-93. https://doi.org/10.1016/j.cell.2010.01.031
  8. Denchi EL and de Lange T (2007). Protection of telomeres through independent control of ATM and ATR by TRF2 and POT1. Nature, 448, 1068-71. https://doi.org/10.1038/nature06065
  9. Fei L, Xiao-Yun P, Shao-Guang H, et al (2012). Expression of hPOT1 in HeLa cells and probability of gene variation of hpot1Exon14 on endometrial cancer are much higher than in other cancers. Asian Pac J Cancer Prev, 13, 5659-63. https://doi.org/10.7314/APJCP.2012.13.11.5659
  10. Feng W, Elaine RP, Arthur JZ, et al (2007). The POT1–TPP1 telomere complex is a telomerase processivity factor. Nature, 445, 506-10. https://doi.org/10.1038/nature05454
  11. Franklin LZ, Luis FZB, Adam F, et al (2012). TPP1 OB-fold domain controls telomere maintenance by recruiting telomerase to chromosome ends. Cell, 150, 481-94. https://doi.org/10.1016/j.cell.2012.07.012
  12. He H, Multani AS, Cosme-Blanco W, et al (2006). POT1b protects telomeres from end-to-end chromosomal fusions and aberrant homologous recombination. EMBO J, 25, 5180-90. https://doi.org/10.1038/sj.emboj.7601294
  13. He H, Wang Y, Guo X, et al (2009). Pot1b deletion and telomerase haploinsufficiency in mice initiate an ATRdependent DNA damage response and elicit phenotypes resembling dyskeratosiscongenita. Mol Cell Biol, 29, 229-40. https://doi.org/10.1128/MCB.01400-08
  14. Hockemeyer D, Daniels JP, Takai H, de Lange T (2006). Recent expansion of the telomeric complex in rodents: Two distinct POT1 proteins protect mouse telomeres. Cell, 126, 63-77. https://doi.org/10.1016/j.cell.2006.04.044
  15. Hockemeyer D, Sfeir AJ, Shay JW, Wright WE, de Lange T (2005). POT1 protects telomeres from a transient DNA damage response and determines how human chromosomes end. EMBO J, 24, 2667-8. https://doi.org/10.1038/sj.emboj.7600733
  16. Hua H, Yang Z, Mei Z, Shuai Y, Xiao- Qiu L (2010). Expression of TRF, TRF2, TIN2, TERT, Ku70, and BRCA1proteins associated with telomere shortening and may contribute to multistage carcinogenesis of gastric cancer. J Cancer Res Clin Oncol, 136, 1407-14. https://doi.org/10.1007/s00432-010-0795-x
  17. Huawei X, Dan L, Zhou S (2008). The telosome/shelterin complex and its functions. Genome Biology, 9, 232. https://doi.org/10.1186/gb-2008-9-9-232
  18. Huichen W, AngeRonel P, Yoshihiko T, et al (2003). Biochemical evidence for Ku-independent backup pathways of NHEJ. Nucleic Acids Research, 31, 5378-88.
  19. Jason AS, Mary FC, Feng W, Carolyn MP (2012). Maintaining the end: Roles of telomere proteins in end protection, telomere replication and length regulation. J Mutation research, 730, 12-9. https://doi.org/10.1016/j.mrfmmm.2011.08.011
  20. Jeffrey ZSY, Dirk H, Andrew NK, et al (2004). POT1-interacting protein PIP1: a telomere length regulator that recruits POT1 to the TIN2/TRF1 complex. Genes Dev, 18, 1649-54. https://doi.org/10.1101/gad.1215404
  21. Jill RD and Titia de L (2007). The role of the poly(ADP-ribose) polymerase tankyrase1 in telomere length control by the TRF1 component of the shelterin complex. J Biol Chem, 282, 22662-7. https://doi.org/10.1074/jbc.M702620200
  22. Jing Y, Christelle L, Serge B, et al (2010). TRF2 and apollo cooperate with Topoisomerase $2{\alpha}$ to protect human telomeres from replicative damage. J Cell, 142, 230-42. https://doi.org/10.1016/j.cell.2010.05.032
  23. John RW, Xu-Dong Z (2012). Post-translational modifications of TRF1 and TRF2 and their roles in telomere maintenance. Mechanisms Ageing Development, 133, 421-33. https://doi.org/10.1016/j.mad.2012.05.002
  24. Jorunn EE and Sigridur KB (2005). Genomic instability and cancer: networks involved in response to DNA damage. Mutation Res, 592, 18-28. https://doi.org/10.1016/j.mrfmmm.2005.05.010
  25. Judith C, Sahn-ho K, Chang-su L, Miguel R (2001). Cellular senescence, cancer and aging: the telomere connection. Exp Gerontology, 36, 1619-37. https://doi.org/10.1016/S0531-5565(01)00160-7
  26. Julieta P, Carmen S, Jorge A, et al (2014). Expression profile of shelterin components in plasma cell disorders. Clinical significance of POT1 overexpression. Blood Cells Molecules Diseases, 52, 134-9. https://doi.org/10.1016/j.bcmd.2013.10.002
  27. Jun L, Chun-Yan X, Shi-Zhong C, et al (2013). Senescence effects of Angelica sinensis polysaccharides on human acute myelogenous leukaemia stem and progenitor cells. Asian Pac J Cancer Prev, 14, 6549-56. https://doi.org/10.7314/APJCP.2013.14.11.6549
  28. Kaori KT, Tatsuya K, Jill RD, David F, Titia de L (2011). Telomere Protection by TPP1/POT1 Requires Tethering to TIN2. Molecular Cell, 44, 647-59. https://doi.org/10.1016/j.molcel.2011.08.043
  29. Karel R, Michelle LH, Dorothy ES (2006). The role of the non homologous end-joining DNA double-strand break repair pathway in telomere biology. Ann Rev Genetics, 40, 237-77. https://doi.org/10.1146/annurev.genet.39.110304.095755
  30. Kelleher C, Kurth I, Lingner J (2005). Human protection of telomeres 1 (POT1) is a negative regulator of telomerase activity in vitro. Mol Cell Biol, 25, 808-18. https://doi.org/10.1128/MCB.25.2.808-818.2005
  31. Kentaro H, Toshio S, Fumio A (2013). Shelterin component protection of telomeres 1 (Pot1) plays a critical role in the self-renewal of HSCs. Exp Hematology, 41, 37.
  32. Kim SH, Beausejour C, Davalos AR, et al (2004). TIN2 mediates functions of TRF2 at human telomeres. J Biol Chem, 279, 43799-804. https://doi.org/10.1074/jbc.M408650200
  33. Lei M, Podell ER, Cech TR (2004). Structure of human POT1 bound to telomeric single-stranded DNA provides a model for chromosome end-protection. Nat Struct Mol Biol, 11, 1223-9. https://doi.org/10.1038/nsmb867
  34. Lingjun M, Joseph KH, Qubo Z, Tao L, Robert YLT (2011). Nucleostemin inhibits TRF1 dimerization and shortens its dynamic association with the telomere. J Cell Science, 124, 3706-14. https://doi.org/10.1242/jcs.089672
  35. Liu D, Safari A, O'Connor MS, et al (2004). PTOP interacts with POT1 and regulates its localization to telomeres. Nat Cell Biol, 6, 673-80. https://doi.org/10.1038/ncb1142
  36. Liu H, Qin-Qin W, Wen-Bo W, et al (2013). Suppression of Ku80 correlates with Radio-sensitivity and Telomere Shortening in the U2OS telomere-negative osteosarcoma cell line. Asian Pac J Cancer Prev, 14, 795-99. https://doi.org/10.7314/APJCP.2013.14.2.795
  37. Liuh-Yow C, Dan L, Zhou S (2007). Telomere maintenance through spatial control of telomeric proteins. Mol Cell Biol, 27, 5898. https://doi.org/10.1128/MCB.00603-07
  38. Liuh-Yow C, Yi Z, Qinfen Z, et al (2012). Mitochondrial localization of telomeric protein TIN2 links telomere regulation to metabolic control. Molecular Cell, 47, 839-50. https://doi.org/10.1016/j.molcel.2012.07.002
  39. Louise F, Lynda C, Heidi M, Titia de L, Daniela R (2001). Structure of the TRFH dimerization domain of the human telomeric proteins TRF1 and TRF2. Molecular Cell, 8, 351-61. https://doi.org/10.1016/S1097-2765(01)00321-5
  40. Masafumi N, Xiao ZZ, Shuji K, Kun PL (2002). Involvement of the telomeric protein Pin2/TRF1 in the regulation of the mitotic spindle. FEBS Letters, 514, 193-8. https://doi.org/10.1016/S0014-5793(02)02363-3
  41. Michael G, Charles L (2013). A comprehensive model for the recognition of human telomeres by TRF1. J Mol Biol, 425, 2910-21. https://doi.org/10.1016/j.jmb.2013.05.005
  42. Moretti P, Freeman K, Coodly L (1994). Evidence that a complex of SIR proteins interacts with the silencer and telomere binding protein RAP1. Genes Dev, 8, 2257-69. https://doi.org/10.1101/gad.8.19.2257
  43. Munoz P, Raquel B, Maria AB (2006). Perspective Role of the TRF2 telomeric protein in cancer and ageing. J Cell Cycle, 5, 718-21. https://doi.org/10.4161/cc.5.7.2636
  44. O'Connor MS, Amin S, Huawei X, Dan L, Zhou S (2006). A critical role for TPP1 and TIN2 interaction in high-order telomeric complex assembly. Proc Natl Acad Sci USA, 103, 11874-9. https://doi.org/10.1073/pnas.0605303103
  45. Paula M and Maria AB (2010). Role of shelterin in cancer and aging. J Aging Cell, 9, 653-66. https://doi.org/10.1111/j.1474-9726.2010.00596.x
  46. Qian C and Jiandong C (2010). Mechanism of p53 stabilization by ATM after DNA damage. Cell Cycle, 9, 472-8. https://doi.org/10.4161/cc.9.3.10556
  47. Qingqing H, Ping Z, Jia-Heng T, et al (2014). G-quadruplexmediated regulation of telomere binding protein POT1 gene expression. Biochim Biophys Acta, 1840, 2222-33. https://doi.org/10.1016/j.bbagen.2014.03.001
  48. Raffaella D, Diego L (2011). Shelterin complex and associated factors at human telomeres Landes Bioscience. Nucleus, 2, 119-35. https://doi.org/10.4161/nucl.2.2.15135
  49. Rekha R, Hong Z, Hua H, et al (2010). The function of classical and alternative non homologous end-joining pathways in the fusion of dysfunctional telomeres. The EMBO J, 29, 2598-610. https://doi.org/10.1038/emboj.2010.142
  50. Savage SA, Giri N, Baerlocher GM, et al (2008). TINF2, a component of the shelterin telomere protection complex, is mutated in dyskeratosiscongenita. Am J Hum Genet, 82, 501-9. https://doi.org/10.1016/j.ajhg.2007.10.004
  51. ShujiK, Xiao ZZ, Yael Z, et al (2001). Telomeric protein Pin2/TRF1 as an important ATM target in response to double strand DNA breaks. J Biological Chemistry, 276, 29282-1. https://doi.org/10.1074/jbc.M011534200
  52. Sullivan LB, Santos JH, Chandel NS (2012). Mitochondria and telomeres: the promiscuous roles of TIN2. Molecular Cell, 47, 823-4. https://doi.org/10.1016/j.molcel.2012.09.006
  53. Tatsuya K, Gail AO, Catherine EK, Titia de L (2010). Telomere Protection by TPP1 Is Mediated by POT1a and POT1b. Mol Cell Biol, 30, 1059-66. https://doi.org/10.1128/MCB.01498-09
  54. Greider CW (1999). Telomeres do d-loop–t-loop. Cell, 97, 419-22. https://doi.org/10.1016/S0092-8674(00)80750-3
  55. Titia de L (2005). Shelterin: The protein complex that shapes and safeguards human telomeres. Genes Dev, 19, 2100-10. https://doi.org/10.1101/gad.1346005
  56. Veldman T, Etheridge KT, Counter CM (2004). Loss of hPot1 function leads to telomere instability and a cut-like phenotype. Curr Biol, 14, 2264-70. https://doi.org/10.1016/j.cub.2004.12.031
  57. Xiao N, Chen S, Ma Y, et al (2012). Interaction of Berberine derivative with protein POT1 affects telomere function in cancer cells. BBRC, 419, 567-72
  58. Xiao ZZ, Kilian P, Kun PL (2003). Role of Pin2/TRF1 in telomere maintenance and cell cycle control. J cellular biochemistry, 89, 19-37. https://doi.org/10.1002/jcb.10496
  59. Xiaolan G, Yibin D, Yahong L, et al (2007). Dysfunctional telomeres activate an ATM-ATR-dependent DNA damage response to suppress tumorigenesis. The EMBO Journal, 26, 4709-19. https://doi.org/10.1038/sj.emboj.7601893
  60. Xiaoping T, Bo C, Xiaochuan L (2009). Telomere and telomerase as targets for cancer therapy. Appl Biochem Biotechnol, 160, 1460-72.
  61. Xin H, Dan L, Yi Z, et al (2013). AKT regulates TPP1 homodimerization and telomere protection. Aging Cell, 12, 1091-9. https://doi.org/10.1111/acel.12137
  62. Ye JZ, Donigian JR, van Overbeek M, et al (2004). TIN2 binds TRF1 and TRF2 simultaneously and stabilizes the TRF2 complex on telomeres. J Biol Chem, 279, 47264-71. https://doi.org/10.1074/jbc.M409047200
  63. Yi Z, Liuh-Yow C, Xin H, et al (2012). Phosphorylation of TPP1 regulates cell cycle-dependent telomerase recruitment. Proc Natl Acad Sci USA, 110, 5457-62.
  64. Yoon RH and In KC (2009).Ubiquitin ligase RLIM modulates telomere length homeostasis through a proteolysis of TRF1. J Biol Chem, 284, 8557-66. https://doi.org/10.1074/jbc.M806702200

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