1932

Abstract

Members of the FET protein family, consisting of FUS, EWSR1, and TAF15, bind to RNA and contribute to the control of transcription, RNA processing, and the cytoplasmic fates of messenger RNAs in metazoa. FET proteins can also bind DNA, which may be important in transcription and DNA damage responses. FET proteins are of medical interest because chromosomal rearrangements of their genes promote various sarcomas and because point mutations in FUS or TAF15 can cause neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal lobar dementia. Recent results suggest that both the normal and pathological effects of FET proteins are modulated by low-complexity or prion-like domains, which can form higher-order assemblies with novel interaction properties. Herein, we review FET proteins with an emphasis on how the biochemical properties of FET proteins may relate to their biological functions and to pathogenesis.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-biochem-060614-034325
2015-06-02
2024-04-18
Loading full text...

Full text loading...

/deliver/fulltext/biochem/84/1/annurev-biochem-060614-034325.html?itemId=/content/journals/10.1146/annurev-biochem-060614-034325&mimeType=html&fmt=ahah

Literature Cited

  1. Eberle AB, Visa N. 1.  2014. Quality control of mRNP biogenesis: networking at the transcription site. Semin. Cell Dev. Biol. 32C:37–46 [Google Scholar]
  2. Saguez C, Olesen JR, Jensen TH. 2.  2005. Formation of export-competent mRNP: escaping nuclear destruction. Curr. Opin. Cell Biol. 17:287–93 [Google Scholar]
  3. Moore MJ, Proudfoot NJ. 3.  2009. Pre-mRNA processing reaches back to transcription and ahead to translation. Cell 136:688–700 [Google Scholar]
  4. Hilleren P, Parker R. 4.  1999. Mechanisms of mRNA surveillance in eukaryotes. Annu. Rev. Genet. 33:229–60 [Google Scholar]
  5. Mitchell SF, Parker R. 5.  2014. Principles and properties of eukaryotic mRNPs. Mol. Cell 54:547–58 [Google Scholar]
  6. Müller-McNicoll M, Neugebauer KM. 6.  2013. How cells get the message: dynamic assembly and function of mRNA–protein complexes. Nat. Rev. Genet. 14:275–87 [Google Scholar]
  7. Castello A, Fischer B, Eichelbaum K, Horos R, Beckmann BM. 7.  et al. 2012. Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 149:1393–406 [Google Scholar]
  8. Piñol-Roma S, Dreyfuss G. 8.  1992. Shuttling of pre-mRNA binding proteins between nucleus and cytoplasm. Nature 355:730–32 [Google Scholar]
  9. Piñol-Roma S, Dreyfuss G. 9.  1993. hnRNP proteins: localization and transport between the nucleus and the cytoplasm. Trends Cell Biol. 3:151–55 [Google Scholar]
  10. Lau JS, Baumeister P, Kim E, Roy B, Hsieh TY. 10.  et al. 2000. Heterogeneous nuclear ribonucleoproteins as regulators of gene expression through interactions with the human thymidine kinase promoter. J. Cell Biochem. 79:395–406 [Google Scholar]
  11. Tomonaga T, Levens D. 11.  1995. Heterogeneous nuclear ribonucleoprotein K is a DNA-binding transactivator. J. Biol. Chem. 270:4875–81 [Google Scholar]
  12. Miau LH, Chang CJ, Shen BJ, Tsai WH, Lee SC. 12.  1998. Identification of heterogeneous nuclear ribonucleoprotein K (hnRNP K) as a repressor of C/EBPβ-mediated gene activation. J. Biol. Chem. 273:10784–91 [Google Scholar]
  13. Riggi N, Cironi L, Suva ML, Stamenkovic I. 13.  2007. Sarcomas: genetics, signalling, and cellular origins. Part 1: The fellowship of TET. J. Pathol. 213:4–20 [Google Scholar]
  14. Tan AY, Manley JL. 14.  2009. The TET family of proteins: functions and roles in disease. J. Mol. Cell Biol. 1:82–92 [Google Scholar]
  15. Han TW, Kato M, Xie S, Wu LC, Mirzaei H. 15.  et al. 2012. Cell-free formation of RNA granules: Bound RNAs identify features and components of cellular assemblies. Cell 149:768–79 [Google Scholar]
  16. Kato M, Han TW, Xie S, Shi K, Du X. 16.  et al. 2012. Cell-free formation of RNA granules: Low complexity sequence domains form dynamic fibers within hydrogels. Cell 149:753–67 [Google Scholar]
  17. Kwon I, Kato M, Xiang S, Wu L, Theodoropoulos P. 17.  et al. 2013. Phosphorylation-regulated binding of RNA polymerase II to fibrous polymers of low-complexity domains. Cell 155:1049–60 [Google Scholar]
  18. Schwartz JC, Wang X, Podell ER, Cech TR. 18.  2013. RNA seeds higher-order assembly of FUS protein. Cell Rep. 5:918–25 [Google Scholar]
  19. Kovar H. 19.  2011. Dr. Jekyll and Mr. Hyde: the two faces of the FUS/EWS/TAF15 protein family. Sarcoma 2011:837474 [Google Scholar]
  20. Lagier-Tourenne C, Cleveland DW. 20.  2009. Rethinking ALS: the FUS about TDP-43. Cell 136:1001–4 [Google Scholar]
  21. Mackenzie IR, Rademakers R, Neumann M. 21.  2010. TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia. Lancet Neurol. 9:995–1007 [Google Scholar]
  22. Bertolotti A, Lutz Y, Heard DJ, Chambon P, Tora L. 22.  1996. hTAF(II)68, a novel RNA/ssDNA-binding protein with homology to the pro-oncoproteins TLS/FUS and EWS is associated with both TFIID and RNA polymerase II. EMBO J. 15:5022–31 [Google Scholar]
  23. Liu X, Niu C, Ren J, Zhang J, Xie X. 23.  et al. 2013. The RRM domain of human fused in sarcoma protein reveals a non-canonical nucleic acid binding site. Biochim. Biophys. Acta 1832:375–85 [Google Scholar]
  24. Xu RM, Jokhan L, Cheng X, Mayeda A, Krainer AR. 24.  1997. Crystal structure of human UP1, the domain of hnRNP A1 that contains two RNA-recognition motifs. Structure 5:559–70 [Google Scholar]
  25. Ding J, Hayashi MK, Zhang Y, Manche L, Krainer AR, Xu RM. 25.  1999. Crystal structure of the two-RRM domain of hnRNP A1 (UP1) complexed with single-stranded telomeric DNA. Genes Dev. 13:1102–15 [Google Scholar]
  26. Iko Y, Kodama TS, Kasai N, Oyama T, Morita EH. 26.  et al. 2004. Domain architectures and characterization of an RNA-binding protein, TLS. J. Biol. Chem. 279:44834–40 [Google Scholar]
  27. Shamoo Y, Krueger U, Rice LM, Williams KR, Steitz TA. 27.  1997. Crystal structure of the two RNA binding domains of human hnRNP A1 at 1.75 Å resolution. Nat. Struct. Biol. 4:215–22 [Google Scholar]
  28. Reijns MA, Alexander RD, Spiller MP, Beggs JD. 28.  2008. A role for Q/N-rich aggregation-prone regions in P-body localization. J. Cell Sci. 121:2463–72 [Google Scholar]
  29. Decker CJ, Teixeira D, Parker R. 29.  2007. Edc3p and a glutamine/asparagine-rich domain of Lsm4p function in processing body assembly in Saccharomyces cerevisiae. J. Cell Biol. 179:437–49 [Google Scholar]
  30. Gilks N, Kedersha N, Ayodele M, Shen L, Stoecklin G. 30.  et al. 2004. Stress granule assembly is mediated by prion-like aggregation of TIA-1. Mol. Biol. Cell 15:5383–98 [Google Scholar]
  31. King OD, Gitler AD, Shorter J. 31.  2012. The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease. Brain Res.146261–80
  32. Calvio C, Neubauer G, Mann M, Lamond AI. 32.  1995. Identification of hnRNP P2 as TLS/FUS using electrospray mass spectrometry. RNA 1:724–33 [Google Scholar]
  33. Takahama K, Kino K, Arai S, Kurokawa R, Oyoshi T. 33.  2011. Identification of Ewing's sarcoma protein (EWS) as a G-quadruplex DNA- and RNA-binding protein. FEBS J. 278:988–98 [Google Scholar]
  34. Tan AY, Riley TR, Coady T, Bussemaker HJ, Manley JL. 34.  2012. TLS/FUS (translocated in liposarcoma/fused in sarcoma) regulates target gene transcription via single-stranded DNA response elements. PNAS 109:6040–35 [Google Scholar]
  35. Hackl W, Lührmann R. 35.  1996. Molecular cloning and subcellular localisation of the snRNP-associated protein 69KD, a structural homologue of the proto-oncoproteins TLS and EWS with RNA- and DNA-binding properties. J. Mol. Biol. 264:843–51 [Google Scholar]
  36. Alliegro MC, Alliegro MA. 36.  1996. A nuclear protein regulated during the transition from active to quiescent phenotype in cultured endothelial cells. Dev. Biol. 174:288–97 [Google Scholar]
  37. Schwartz JC, Ebmeier CC, Podell ER, Heimiller J, Taatjes DJ, Cech TR. 37.  2012. FUS binds the CTD of RNA polymerase II and regulates its phosphorylation at Ser2. Genes Dev. 26:2690–95 [Google Scholar]
  38. Zinszner H, Sok J, Immanuel D, Yin Y, Ron D. 38.  1997. TLS (FUS) binds RNA in vivo and engages in nucleo-cytoplasmic shuttling. J. Cell Sci. 110:1741–50 [Google Scholar]
  39. Perrotti D, Iervolino A, Cesi V, Cirinna M, Lombardini S. 39.  et al. 2000. BCR-ABL prevents c-Jun-mediated and proteasome-dependent FUS (TLS) proteolysis through a protein kinase CβII–dependent pathway. Mol. Cell. Biol. 20:6159–69 [Google Scholar]
  40. Gardiner M, Toth R, Vandermoere F, Morrice NA, Rouse J. 40.  2008. Identification and characterization of FUS/TLS as a new target of ATM. Biochem. J. 415:297–307 [Google Scholar]
  41. Guipaud O, Guillonneau F, Labas V, Praseuth D, Rossier J. 41.  et al. 2006. An in vitro enzymatic assay coupled to proteomics analysis reveals a new DNA processing activity for Ewing sarcoma and TAF(II)68 proteins. Proteomics 6:5962–72 [Google Scholar]
  42. Bertrand P, Akhmedov AT, Delacote F, Durrbach A, Lopez BS. 42.  1999. Human POMp75 is identified as the pro-oncoprotein TLS/FUS: Both POMp75 and POMp100 DNA homologous pairing activities are associated to cell proliferation. Oncogene 18:4515–21 [Google Scholar]
  43. Baechtold H, Kuroda M, Sok J, Ron D, Lopez BS, Akhmedov AT. 43.  1999. Human 75-kDa DNA-pairing protein is identical to the pro-oncoprotein TLS/FUS and is able to promote D-loop formation. J. Biol. Chem. 274:34337–42 [Google Scholar]
  44. Crozat A, Aman P, Mandahl N, Ron D. 44.  1993. Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma. Nature 363:640–44 [Google Scholar]
  45. Zinszner H, Albalat R, Ron D. 45.  1994. A novel effector domain from the RNA-binding protein TLS or EWS is required for oncogenic transformation by CHOP. Genes Dev. 8:2513–26 [Google Scholar]
  46. Immanuel D, Zinszner H, Ron D. 46.  1995. Association of SARFH (sarcoma-associated RNA-binding fly homolog) with regions of chromatin transcribed by RNA polymerase II. Mol. Cell. Biol. 15:4562–71 [Google Scholar]
  47. Bertolotti A, Melot T, Acker J, Vigneron M, Delattre O, Tora L. 47.  1998. EWS, but not EWS–FLI-1, is associated with both TFIID and RNA polymerase II: interactions between two members of the TET family, EWS and hTAFII68, and subunits of TFIID and RNA polymerase II complexes. Mol. Cell. Biol. 18:1489–97 [Google Scholar]
  48. Ohno T, Ouchida M, Lee L, Gatalica Z, Rao VN, Reddy ES. 48.  1994. The EWS gene, involved in Ewing family of tumors, malignant melanoma of soft parts and desmoplastic small round cell tumors, codes for an RNA binding protein with novel regulatory domains. Oncogene 9:3087–97 [Google Scholar]
  49. Ichikawa H, Shimizu K, Hayashi Y, Ohki M. 49.  1994. An RNA-binding protein gene, TLS/FUS, is fused to ERG in human myeloid leukemia with t(16;21) chromosomal translocation. Cancer Res. 54:2865–68 [Google Scholar]
  50. Lerga A, Hallier M, Delva L, Orvain C, Gallais I. 50.  et al. 2001. Identification of an RNA binding specificity for the potential splicing factor TLS. J. Biol. Chem. 276:6807–16 [Google Scholar]
  51. Hoell JI, Larsson E, Runge S, Nusbaum JD, Duggimpudi S. 51.  et al. 2011. RNA targets of wild-type and mutant FET family proteins. Nat. Struct. Mol. Biol. 18:1428–31 [Google Scholar]
  52. Yamazaki T, Chen S, Yu Y, Yan B, Haertlein TC. 52.  et al. 2012. FUS–SMN protein interactions link the motor neuron diseases ALS and SMA. Cell Rep. 2:799–806 [Google Scholar]
  53. Wang X, Arai S, Song X, Reichart D, Du K. 53.  et al. 2008. Induced ncRNAs allosterically modify RNA-binding proteins in cis to inhibit transcription. Nature 454:126–30 [Google Scholar]
  54. Colombrita C, Onesto E, Megiorni F, Pizzuti A, Baralle FE. 54.  et al. 2012. TDP-43 and FUS RNA-binding proteins bind distinct sets of cytoplasmic messenger RNAs and differently regulate their post-transcriptional fate in motoneuron-like cells. J. Biol. Chem. 287:15636–47 [Google Scholar]
  55. Ishigaki S, Masuda A, Fujioka Y, Iguchi Y, Katsuno M. 55.  et al. 2012. Position-dependent FUS–RNA interactions regulate alternative splicing events and transcriptions. Sci. Rep. 2:529 [Google Scholar]
  56. Daigle JG, Lanson NA Jr, Smith RB, Casci I, Maltare A. 56.  et al. 2013. RNA-binding ability of FUS regulates neurodegeneration, cytoplasmic mislocalization and incorporation into stress granules associated with FUS carrying ALS-linked mutations. Hum. Mol. Genet. 22:1193–205 [Google Scholar]
  57. Rogelj B, Easton LE, Bogu GK, Stanton LW, Rot G. 57.  et al. 2012. Widespread binding of FUS along nascent RNA regulates alternative splicing in the brain. Sci. Rep. 2:603 [Google Scholar]
  58. Lagier-Tourenne C, Polymenidou M, Hutt KR, Vu AQ, Baughn M. 58.  et al. 2012. Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs. Nat. Neurosci. 15:1488–97 [Google Scholar]
  59. Takahama K, Oyoshi T. 59.  2013. Specific binding of modified RGG domain in TLS/FUS to G-quadruplex RNA: Tyrosines in RGG domain recognize 2′-OH of the riboses of loops in G-quadruplex. J. Am. Chem. Soc. 135:18016–19 [Google Scholar]
  60. Ray D, Kazan H, Cook KB, Weirauch MT, Najafabadi HS. 60.  et al. 2013. A compendium of RNA-binding motifs for decoding gene regulation. Nature 499:172–77 [Google Scholar]
  61. Sun Z, Diaz Z, Fang X, Hart MP, Chesi A. 61.  et al. 2011. Molecular determinants and genetic modifiers of aggregation and toxicity for the ALS disease protein FUS/TLS. PLOS Biol. 9:e1000614 [Google Scholar]
  62. Doi H, Okamura K, Bauer PO, Furukawa Y, Shimizu H. 62.  et al. 2008. RNA-binding protein TLS is a major nuclear aggregate–interacting protein in huntingtin exon 1 with expanded polyglutamine-expressing cells. J. Biol. Chem. 283:6489–500 [Google Scholar]
  63. Shaw DJ, Morse R, Todd AG, Eggleton P, Lorson CL, Young PJ. 63.  2010. Identification of a self-association domain in the Ewing's sarcoma protein: a novel function for arginine–glycine–glycine rich motifs?. J. Biochem. 147:885–93 [Google Scholar]
  64. Vance C, Scotter EL, Nishimura AL, Troakes C, Mitchell JC. 64.  et al. 2013. ALS mutant FUS disrupts nuclear localization and sequesters wild-type FUS within cytoplasmic stress granules. Hum. Mol. Genet. 22:2676–88 [Google Scholar]
  65. Yamaguchi A, Kitajo K. 65.  2012. The effect of PRMT1-mediated arginine methylation on the subcellular localization, stress granules, and detergent-insoluble aggregates of FUS/TLS. PLOS ONE 7:e49267 [Google Scholar]
  66. Mackenzie IR, Munoz DG, Kusaka H, Yokota O, Ishihara K. 66.  et al. 2011. Distinct pathological subtypes of FTLD-FUS. Acta Neuropathol. 121:207–18 [Google Scholar]
  67. Bosco DA, Lemay N, Ko HK, Zhou H, Burke C. 67.  et al. 2010. Mutant FUS proteins that cause amyotrophic lateral sclerosis incorporate into stress granules. Hum. Mol. Genet. 19:4160–75 [Google Scholar]
  68. Vance C, Rogelj B, Hortobagyi T, De Vos KJ, Nishimura AL. 68.  et al. 2009. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323:1208–11 [Google Scholar]
  69. Kwiatkowski TJ Jr, Bosco DA, Leclerc AL, Tamrazian E, Vanderburg CR. 69.  et al. 2009. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323:1205–8 [Google Scholar]
  70. Ju S, Tardiff DF, Han H, Divya K, Zhong Q. 70.  et al. 2011. A yeast model of FUS/TLS-dependent cytotoxicity. PLOS Biol. 9:e1001052 [Google Scholar]
  71. Saito R, Smoot ME, Ono K, Ruscheinski J, Wang PL. 71.  et al. 2012. A travel guide to Cytoscape plugins. Nat. Methods 9:1069–76 [Google Scholar]
  72. Ballarino M, Jobert L, Dembele D, de la Grange P, Auboeuf D, Tora L. 72.  2013. TAF15 is important for cellular proliferation and regulates the expression of a subset of cell cycle genes through miRNAs. Oncogene 32:4646–55 [Google Scholar]
  73. Morlando M, Dini Modigliani S, Torrelli G, Rosa A, Di Carlo V. 73.  et al. 2012. FUS stimulates microRNA biogenesis by facilitating co-transcriptional Drosha recruitment. EMBO J. 31:4502–10 [Google Scholar]
  74. Thomsen C, Grundevik P, Elias P, Stahlberg A, Aman P. 74.  2013. A conserved N-terminal motif is required for complex formation between FUS, EWSR1, TAF15 and their oncogenic fusion proteins. FASEB J. 27:4965–74 [Google Scholar]
  75. Korennykh AV, Egea PF, Korostelev AA, Finer-Moore J, Zhang C. 75.  et al. 2009. The unfolded protein response signals through high-order assembly of Ire1. Nature 457:687–93 [Google Scholar]
  76. Lyumkis D, Talley H, Stewart A, Shah S, Park CK. 76.  et al. 2013. Allosteric regulation of DNA cleavage and sequence-specificity through run-on oligomerization. Structure 21:1848–58 [Google Scholar]
  77. Araya N, Hirota K, Shimamoto Y, Miyagishi M, Yoshida E. 77.  et al. 2003. Cooperative interaction of EWS with CREB-binding protein selectively activates hepatocyte nuclear factor 4–mediated transcription. J. Biol. Chem. 278:5427–32 [Google Scholar]
  78. Lee J, Rhee BK, Bae GY, Han YM, Kim J. 78.  2005. Stimulation of Oct-4 activity by Ewing's sarcoma protein. Stem Cells 23:738–51 [Google Scholar]
  79. Tan AY, Manley JL. 79.  2010. TLS inhibits RNA polymerase III transcription. Mol. Cell. Biol. 30:186–96 [Google Scholar]
  80. Yang L, Embree LJ, Hickstein DD. 80.  2000. TLS–ERG leukemia fusion protein inhibits RNA splicing mediated by serine–arginine proteins. Mol. Cell. Biol. 20:3345–54 [Google Scholar]
  81. Chansky HA, Hu M, Hickstein DD, Yang L. 81.  2001. Oncogenic TLS/ERG and EWS/FLI-1 fusion proteins inhibit RNA splicing mediated by YB-1 protein. Cancer Res. 61:3586–90 [Google Scholar]
  82. Das R, Yu J, Zhang Z, Gygi MP, Krainer AR. 82.  et al. 2007. SR proteins function in coupling RNAP II transcription to pre-mRNA splicing. Mol. Cell 26:867–81 [Google Scholar]
  83. Rabbitts TH, Forster A, Larson R, Nathan P. 83.  1993. Fusion of the dominant negative transcription regulator CHOP with a novel gene FUS by translocation t(12;16) in malignant liposarcoma. Nat. Genet. 4:175–80 [Google Scholar]
  84. Panagopoulos I, Aman P, Fioretos T, Hoglund M, Johansson B. 84.  et al. 1994. Fusion of the FUS gene with ERG in acute myeloid leukemia with t(16;21)(p11;q22). Genes Chromosomes Cancer 11:256–62 [Google Scholar]
  85. Law WJ, Cann KL, Hicks GG. 85.  2006. TLS, EWS and TAF15: a model for transcriptional integration of gene expression. Brief Funct. Genomics Proteomics 5:8–14 [Google Scholar]
  86. Zhang D, Paley AJ, Childs G. 86.  1998. The transcriptional repressor ZFM1 interacts with and modulates the ability of EWS to activate transcription. J. Biol. Chem. 273:18086–91 [Google Scholar]
  87. May WA, Lessnick SL, Braun BS, Klemsz M, Lewis BC. 87.  et al. 1993. The Ewing's sarcoma EWS/FLI-1 fusion gene encodes a more potent transcriptional activator and is a more powerful transforming gene than FLI-1. Mol. Cell. Biol. 13:7393–98 [Google Scholar]
  88. Bertolotti A, Bell B, Tora L. 88.  1999. The N-terminal domain of human TAFII68 displays transactivation and oncogenic properties. Oncogene 18:8000–10 [Google Scholar]
  89. Hancock JD, Lessnick SL. 89.  2008. A transcriptional profiling meta-analysis reveals a core EWSFLI gene expression signature. Cell Cycle 7:250–56 [Google Scholar]
  90. Zou J, Ichikawa H, Blackburn ML, Hu HM, Zielinska-Kwiatkowska A. 90.  et al. 2005. The oncogenic TLS–ERG fusion protein exerts different effects in hematopoietic cells and fibroblasts. Mol. Cell. Biol. 25:6235–46 [Google Scholar]
  91. Kuroda M, Sok J, Webb L, Baechtold H, Urano F. 91.  et al. 2000. Male sterility and enhanced radiation sensitivity in TLS−/−mice. EMBO J. 19:453–62 [Google Scholar]
  92. Powers CA, Mathur M, Raaka BM, Ron D, Samuels HH. 92.  1998. TLS (translocated-in-liposarcoma) is a high-affinity interactor for steroid, thyroid hormone, and retinoid receptors. Mol. Endocrinol. 12:4–18 [Google Scholar]
  93. Perrotti D, Bonatti S, Trotta R, Martinez R, Skorski T. 93.  et al. 1998. TLS/FUS, a pro-oncogene involved in multiple chromosomal translocations, is a novel regulator of BCR/ABL-mediated leukemogenesis. EMBO J. 17:4442–55 [Google Scholar]
  94. Deloulme JC, Prichard L, Delattre O, Storm DR. 94.  1997. The prooncoprotein EWS binds calmodulin and is phosphorylated by protein kinase C through an IQ domain. J. Biol. Chem. 272:27369–77 [Google Scholar]
  95. Bachmaier R, Aryee DN, Jug G, Kauer M, Kreppel M. 95.  et al. 2009. O-GlcNAcylation is involved in the transcriptional activity of EWS–FLI1 in Ewing's sarcoma. Oncogene 28:1280–84 [Google Scholar]
  96. Jobert L, Argentini M, Tora L. 96.  2009. PRMT1 mediated methylation of TAF15 is required for its positive gene regulatory function. Exp. Cell Res. 315:1273–86 [Google Scholar]
  97. Araya N, Hiraga H, Kako K, Arao Y, Kato S, Fukamizu A. 97.  2005. Transcriptional down-regulation through nuclear exclusion of EWS methylated by PRMT1. Biochem. Biophys. Res. Commun. 329:653–60 [Google Scholar]
  98. Belyanskaya LL, Delattre O, Gehring H. 98.  2003. Expression and subcellular localization of Ewing sarcoma (EWS) protein is affected by the methylation process. Exp. Cell Res. 288:374–81 [Google Scholar]
  99. Yang L, Chansky HA, Hickstein DD. 99.  2000. EWS.Fli1 fusion protein interacts with hyperphosphorylated RNA polymerase II and interferes with serine–arginine protein-mediated RNA splicing. J. Biol. Chem. 275:37612–18 [Google Scholar]
  100. Hallier M, Lerga A, Barnache S, Tavitian A, Moreau-Gachelin F. 100.  1998. The transcription factor Spi-1/PU.1 interacts with the potential splicing factor TLS. J. Biol. Chem. 273:4838–42 [Google Scholar]
  101. Uranishi H, Tetsuka T, Yamashita M, Asamitsu K, Shimizu M. 101.  et al. 2001. Involvement of the pro-oncoprotein TLS (translocated in liposarcoma) in nuclear factor κB p65–mediated transcription as a coactivator. J. Biol. Chem. 276:13395–401 [Google Scholar]
  102. Pérez-Losada J, Sánchez-Martín M, Rodríguez-García MA, Pérez-Mancera PA, Pintado B. 102.  et al. 2000. Liposarcoma initiated by FUS/TLS-CHOP: The FUS/TLS domain plays a critical role in the pathogenesis of liposarcoma. Oncogene 19:6015–22 [Google Scholar]
  103. Ichikawa H, Shimizu K, Katsu R, Ohki M. 103.  1999. Dual transforming activities of the FUS (TLS)–ERG leukemia fusion protein conferred by two N-terminal domains of FUS (TLS). Mol. Cell. Biol. 19:7639–50 [Google Scholar]
  104. Prasad DD, Ouchida M, Lee L, Rao VN, Reddy ES. 104.  1994. TLS/FUS fusion domain of TLS/FUS–erg chimeric protein resulting from the t(16;21) chromosomal translocation in human myeloid leukemia functions as a transcriptional activation domain. Oncogene 9:3717–29 [Google Scholar]
  105. Martini A, La Starza R, Janssen H, Bilhou-Nabera C, Corveleyn A. 105.  et al. 2002. Recurrent rearrangement of the Ewing's sarcoma gene, EWSR1, or its homologue, TAF15, with the transcription factor CIZ/NMP4 in acute leukemia. Cancer Res. 62:5408–12 [Google Scholar]
  106. Kuroda M, Wang X, Sok J, Yin Y, Chung P. 106.  et al. 1999. Induction of a secreted protein by the myxoid liposarcoma oncogene. PNAS 96:5025–30 [Google Scholar]
  107. Braun BS, Frieden R, Lessnick SL, May WA, Denny CT. 107.  1995. Identification of target genes for the Ewing's sarcoma EWS/FLI fusion protein by representational difference analysis. Mol. Cell. Biol. 15:4623–30 [Google Scholar]
  108. Paronetto MP, Minana B, Valcarcel J. 108.  2011. The Ewing sarcoma protein regulates DNA damage–induced alternative splicing. Mol. Cell 43:353–68 [Google Scholar]
  109. Meissner M, Lopato S, Gotzmann J, Sauermann G, Barta A. 109.  2003. Proto-oncoprotein TLS/FUS is associated to the nuclear matrix and complexed with splicing factors PTB, SRM160, and SR proteins. Exp. Cell Res. 283:184–95 [Google Scholar]
  110. Muñoz MJ, Pérez-Santangelo MS, Paronetto MP, de la Mata M, Pelisch F. 110.  et al. 2009. DNA damage regulates alternative splicing through inhibition of RNA polymerase II elongation. Cell 137:708–20 [Google Scholar]
  111. Leichter M, Marko M, Ganou V, Patrinou-Georgoula M, Tora L, Guialis A. 111.  2011. A fraction of the transcription factor TAF15 participates in interactions with a subset of the spliceosomal U1 snRNP complex. Biochim. Biophys. Acta 1814:1812–24 [Google Scholar]
  112. de Hoog CL, Foster LJ, Mann M. 112.  2004. RNA and RNA binding proteins participate in early stages of cell spreading through spreading initiation centers. Cell 117:649–62 [Google Scholar]
  113. Bres V, Yoh SM, Jones KA. 113.  2008. The multi-tasking P-TEFb complex. Curr. Opin. Cell Biol. 20:334–40 [Google Scholar]
  114. Todd AG, Morse R, Shaw DJ, Stebbings H, Young PJ. 114.  2010. Analysis of SMN-neurite granules: Core Cajal body components are absent from SMN–cytoplasmic complexes. Biochem. Biophys. Res. Commun. 397:479–85 [Google Scholar]
  115. Tsuiji H, Iguchi Y, Furuya A, Kataoka A, Hatsuta H. 115.  et al. 2013. Spliceosome integrity is defective in the motor neuron diseases ALS and SMA. EMBO Mol. Med. 5:221–34 [Google Scholar]
  116. Mackenzie IR, Neumann M. 116.  2012. FET proteins in frontotemporal dementia and amyotrophic lateral sclerosis. Brain Res. 1462:40–43 [Google Scholar]
  117. Neumann M, Bentmann E, Dormann D, Jawaid A, DeJesus-Hernandez M. 117.  et al. 2011. FET proteins TAF15 and EWS are selective markers that distinguish FTLD with FUS pathology from amyotrophic lateral sclerosis with FUS mutations. Brain 134:2595–609 [Google Scholar]
  118. Leemann-Zakaryan RP, Pahlich S, Grossenbacher D, Gehring H. 118.  2011. Tyrosine phosphorylation in the C-terminal nuclear localization and retention signal (C-NLS) of the EWS protein. Sarcoma 2011:218483 [Google Scholar]
  119. Zhang ZC, Chook YM. 119.  2012. Structural and energetic basis of ALS-causing mutations in the atypical proline–tyrosine nuclear localization signal of the Fused in Sarcoma protein (FUS). PNAS 109:12017–21 [Google Scholar]
  120. Dormann D, Madl T, Valori CF, Bentmann E, Tahirovic S. 120.  et al. 2012. Arginine methylation next to the PY-NLS modulates Transportin binding and nuclear import of FUS. EMBO J. 31:4258–75 [Google Scholar]
  121. Scaramuzzino C, Monaghan J, Milioto C, Lanson NA Jr, Maltare A. 121.  et al. 2013. Protein arginine methyltransferase 1 and 8 interact with FUS to modify its sub-cellular distribution and toxicity in vitro and in vivo. PLOS ONE 8:e61576 [Google Scholar]
  122. Tradewell ML, Yu Z, Tibshirani M, Boulanger MC, Durham HD, Richard S. 122.  2012. Arginine methylation by PRMT1 regulates nuclear–cytoplasmic localization and toxicity of FUS/TLS harbouring ALS-linked mutations. Hum. Mol. Genet. 21:136–49 [Google Scholar]
  123. Belyanskaya LL, Gehrig PM, Gehring H. 123.  2001. Exposure on cell surface and extensive arginine methylation of Ewing sarcoma (EWS) protein. J. Biol. Chem. 276:18681–87 [Google Scholar]
  124. Fujii R, Grossenbacher-Zinchuk O, Jamari I, Wang Y, Zinchuk V, Takumi T. 124.  2009. TLS-GFP cannot rescue mRNP formation near spines and spine phenotype in TLS-KO. Neuroreport 20:57–61 [Google Scholar]
  125. Fujii R, Takumi T. 125.  2005. TLS facilitates transport of mRNA encoding an actin-stabilizing protein to dendritic spines. J. Cell Sci. 118:5755–65 [Google Scholar]
  126. Fujii R, Okabe S, Urushido T, Inoue K, Yoshimura A. 126.  et al. 2005. The RNA binding protein TLS is translocated to dendritic spines by mGluR5 activation and regulates spine morphology. Curr. Biol. 15:587–93 [Google Scholar]
  127. Andersson MK, Ståhlberg A, Arvidsson Y, Olofsson A, Semb H. 127.  et al. 2008. The multifunctional FUS, EWS and TAF15 proto-oncoproteins show cell type–specific expression patterns and involvement in cell spreading and stress response. BMC Cell Biol. 9:37 [Google Scholar]
  128. Yasuda K, Zhang H, Loiselle D, Haystead T, Macara IG, Mili S. 128.  2013. The RNA-binding protein Fus directs translation of localized mRNAs in APC-RNP granules. J. Cell Biol. 203:737–46 [Google Scholar]
  129. Sama RR, Ward CL, Kaushansky LJ, Lemay N, Ishigaki S. 129.  et al. 2013. FUS/TLS assembles into stress granules and is a prosurvival factor during hyperosmolar stress. J. Cell Physiol. 228:2222–31 [Google Scholar]
  130. Li YR, King OD, Shorter J, Gitler AD. 130.  2013. Stress granules as crucibles of ALS pathogenesis. J. Cell Biol. 201:361–72 [Google Scholar]
  131. Ramaswami M, Taylor JP, Parker R. 131.  2013. Altered ribostasis: RNA–protein granules in degenerative disorders. Cell 154:727–36 [Google Scholar]
  132. Blokhuis AM, Groen EJ, Koppers M, van den Berg LH, Pasterkamp RJ. 132.  2013. Protein aggregation in amyotrophic lateral sclerosis. Acta Neuropathol. 125:777–94 [Google Scholar]
  133. Polymenidou M, Lagier-Tourenne C, Hutt KR, Bennett CF, Cleveland DW, Yeo GW. 133.  2012. Misregulated RNA processing in amyotrophic lateral sclerosis. Brain Res. 1462:3–15 [Google Scholar]
  134. Ibrahim F, Nakaya T, Mourelatos Z. 134.  2012. RNA dysregulation in diseases of motor neurons. Annu. Rev. Pathol. Mech. Dis. 7:323–52 [Google Scholar]
  135. Ticozzi N, Vance C, Leclerc AL, Keagle P, Glass JD. 135.  et al. 2011. Mutational analysis reveals the FUS homolog TAF15 as a candidate gene for familial amyotrophic lateral sclerosis. Am. J. Med. Genet. B 156:285–90 [Google Scholar]
  136. Shelkovnikova TA, Robinson HK, Southcombe JA, Ninkina N, Buchman VL. 136.  2014. Multistep process of FUS aggregation in the cell cytoplasm involves RNA-dependent and RNA-independent mechanisms. Hum. Mol. Genet. 23:2511–26 [Google Scholar]
  137. Baron DM, Kaushansky LJ, Ward CL, Sama RR, Chian RJ. 137.  et al. 2013. Amyotrophic lateral sclerosis–linked FUS/TLS alters stress granule assembly and dynamics. Mol. Neurodegener. 8:30 [Google Scholar]
  138. Deng H, Gao K, Jankovic J. 138.  2014. The role of FUS gene variants in neurodegenerative diseases. Nat. Rev. Neurol. 10:337–48 [Google Scholar]
  139. Ticozzi N, Silani V, LeClerc AL, Keagle P, Gellera C. 139.  et al. 2009. Analysis of FUS gene mutation in familial amyotrophic lateral sclerosis within an Italian cohort. Neurology 73:1180–85 [Google Scholar]
  140. Ito D, Seki M, Tsunoda Y, Uchiyama H, Suzuki N. 140.  2010. Nuclear transport impairment of amyotrophic lateral sclerosis–linked mutations in FUS/TLS. Ann. Neurol. 69:152–62 [Google Scholar]
  141. Schwartz JC, Podell ER, Han SSW, Berry JD, Eggan KC, Cech TR. 141.  2014. FUS is sequestered in nuclear aggregates in ALS patient fibroblasts. Mol. Biol. Cell. 25:2571–78 [Google Scholar]
  142. Kabashi E, Bercier V, Lissouba A, Liao M, Brustein E. 142.  et al. 2011. FUS and TARDBP but not SOD1 interact in genetic models of amyotrophic lateral sclerosis. PLOS Genet. 7:e1002214 [Google Scholar]
  143. Qiu H, Lee S, Shang Y, Wang WY, Au KF. 143.  et al. 2014. ALS-associated mutation FUS-R521C causes DNA damage and RNA splicing defects. J. Clin. Investig. 124:981–99 [Google Scholar]
  144. Wang WY, Pan L, Su SC, Quinn EJ, Sasaki M. 144.  et al. 2013. Interaction of FUS and HDAC1 regulates DNA damage response and repair in neurons. Nat. Neurosci. 16:1383–91 [Google Scholar]
  145. Mastrocola AS, Kim SH, Trinh AT, Rodenkirch LA, Tibbetts RS. 145.  2013. The RNA-binding protein fused in sarcoma (FUS) functions downstream of poly(ADP-ribose) polymerase (PARP) in response to DNA damage. J. Biol. Chem. 288:24731–41 [Google Scholar]
  146. Lee HJ, Yoon C, Schmidt B, Park DJ, Zhang AY. 146.  et al. 2013. Combining PARP-1 inhibition and radiation in Ewing sarcoma results in lethal DNA damage. Mol. Cancer Ther. 12:2591–600 [Google Scholar]
  147. Li H, Watford W, Li C, Parmelee A, Bryant MA. 147.  et al. 2007. Ewing sarcoma gene EWS is essential for meiosis and B lymphocyte development. J. Clin. Investig. 117:1314–23 [Google Scholar]
  148. Hicks GG, Singh N, Nashabi A, Mai S, Bozek G. 148.  et al. 2000. Fus deficiency in mice results in defective B-lymphocyte development and activation, high levels of chromosomal instability and perinatal death. Nat. Genet. 24:175–79 [Google Scholar]
  149. Sugawara T, Oguro H, Negishi M, Morita Y, Ichikawa H. 149.  et al. 2010. FET family proto-oncogene Fus contributes to self-renewal of hematopoietic stem cells. Exp. Hematol. 38:696–706 [Google Scholar]
  150. Brenner JC, Feng FY, Han S, Patel S, Goyal SV. 150.  et al. 2012. PARP-1 inhibition as a targeted strategy to treat Ewing's sarcoma. Cancer Res. 72:1608–13 [Google Scholar]
  151. Yoshida K. 151.  2008. Nuclear trafficking of pro-apoptotic kinases in response to DNA damage. Trends Mol. Med. 14:305–13 [Google Scholar]
/content/journals/10.1146/annurev-biochem-060614-034325
Loading
/content/journals/10.1146/annurev-biochem-060614-034325
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error