Structural characteristics of simple RNA repeats associated with disease and their deleterious protein interactions

Frontiers in Cellular Neuroscience

Volumn 11, Issue , 2017, Pages

  Ciesiolka, Adam ^a   Jazurek, Magdalena ^a   Drazkowska, Karolina ^a   Krzyzosiak, Wlodzimierz J ^a  

^a INSTITUTE OF BIOORGANIC CHEMISTRY   (Poland)

Author keywords

Repeat expansion disorders; RNA repeat structures; RNA toxicity; RNA binding proteins; Simple expanded repeats

Indexed keywords

ATAXIN 1; ATAXIN 2; NUCLEOLIN;

AUUCU REPEAT; CAG REPEAT; CCCCGG REPEAT; CGG REPEAT; DNA FLANKING REGION; DNA STRUCTURE; ELECTRON MICROSCOPY; FLUORESCENCE IN SITU HYBRIDIZATION; FRONTOTEMPORAL DEMENTIA; GGGGCC REPEAT; HUMAN; HUNTINGTON CHOREA; IMMUNOBLOTTING; IMMUNOPRECIPITATION; MYOTONIC DYSTROPHY; NUCLEAR MAGNETIC RESONANCE; PROTEIN INTERACTION; REVIEW; SCLEROSIS; SHORT TANDEM REPEAT; SPINOCEREBELLAR DEGENERATION; X RAY CRYSTALLOGRAPHY;

EID: 85018351299     PISSN: 16625102     EISSN: None     Source Type: Journal    
DOI: 10.3389/fncel.2017.00097     Document Type: Review

References (136)

1. Abudayyeh, O. O., Gootenberg, J. S., Konermann, S., Joung, J., Slaymaker, I. M., Cox, D. B. T., et al. (2016). C2c2 is a single-component programmable RNA-guided RNA-targeting CRISPR effector. Science 353:aaf5573. doi: 10.1126/science.aaf5573
2. Almeida, S., Gascon, E., Tran, H., Chou, H. J., Gendron, T. F., Degroot, S., et al. (2013). Modeling key pathological features of frontotemporal dementia with C9ORF72 repeat expansion in iPSC-derived human neurons. Acta Neuropathol. 126, 385-399. doi: 10.1007/s00401-013-1149-y
3. Ascano, M., Hafner, M., Cekan, P., Gerstberger, S., and Tuschl, T. (2012). Identification of RNA-protein interaction networks using PAR-CLIP. Wiley Interdiscip. Rev. RNA 3, 159-177. doi: 10.1002/wrna.1103
4. Ash, P. E. A., Bieniek, K. F., Gendron, T. F., Caulfield, T., Lin, W.-L., DeJesus-Hernandez, M., et al. (2013). Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron 77, 639-646. doi: 10.1016/j.neuron.2013.02.004
5. Aw, J. G. A., Shen, Y., Wilm, A., Sun, M., Lim, X. N., Boon, K. L., et al. (2016). in vivo mapping of eukaryotic RNA interactomes reveals principles of higher-order organization and regulation. Mol. Cell 62, 603-617. doi: 10.1016/j.molcel.2016.04.028
6. Batra, R., Charizanis, K., and Swanson, M. S. (2010). Partners in crime: bidirectional transcription in unstable microsatellite disease. Hum. Mol. Genet. 19, R77-R82. doi: 10.1093/hmg/ddq132
7. Brázda, V., Hároníková, L., Liao, J. C. C., and Fojta, M. (2014). DNA and RNA quadruplex-binding proteins. Int. J. Mol. Sci. 15, 17493-17517. doi: 10.3390/ijms151017493
8. Broda, M., Kierzek, E., Gdaniec, Z., Kulinski, T., and Kierzek, R. (2005). Thermodynamic stability of RNA structures formed by CNG trinucleotide repeats. Implication for prediction of RNA structure. Biochemistry 44, 10873-10882. doi: 10.1021/bi0502339
9. Busan, S., and Weeks, K. M. (2013). Role of context in RNA structure: flanking sequences reconfigure CAG motif folding in huntingtin exon 1 transcripts. Biochemistry 52, 8219-8225. doi: 10.1021/bi401129r
10. Cass, D., Hotchko, R., Barber, P., Jones, K., Gates, D. P., and Berglund, J. A. (2011). The four Zn fingers of MBNL1 provide a flexible platform for recognition of its RNA binding elements. BMC Mol. Biol. 12:20. doi: 10.1186/1471-2199-12-20
11. Chen, X., Wei, S., Ji, Y., Guo, X., and Yang, F. (2015). Quantitative proteomics using SILAC: principles, applications and developments. Proteomics 15, 3175-3192. doi: 10.1002/pmic.201500108
12. Conlon, E. G., Lu, L., Sharma, A., Yamazaki, T., Tang, T., Shneider, N. A., et al. (2016). The C9ORF72 GGGGCC expansion forms RNA G-quadruplex inclusions and sequesters hnRNP H to disrupt splicing in ALS patient brains. Elife 5:e17820. doi: 10.7554/eLife.17820
13. Conway, A. E., Van Nostrand, E. L., Pratt, G. A., Aigner, S., Wilbert, M. L., Sundararaman, B., et al. (2016). Enhanced CLIP uncovers IMP protein-RNA targets in human pluripotent stem cells important for cell adhesion and survival. Cell Rep. 15, 666-679. doi: 10.1016/j.celrep.2016.03.052
14. Coonrod, L. A., Lohman, J. R., and Berglund, J. A. (2012). Utilizing the GAAA tetraloop/receptor to facilitate crystal packing and structure determination of a CUG RNA helix. Biochemistry 51, 8330-8337. doi: 10.1021/bi300829w
15. Cooper-Knock, J., Higginbottom, A., Stopford, M. J., Highley, J. R., Ince, P. G., Wharton, S. B., et al. (2015). Antisense RNA foci in the motor neurons of C9ORF72-ALS patients are associated with TDP-43 proteinopathy. Acta Neuropathol. 130, 63-75. doi: 10.1007/s00401-015-1429-9
16. DeJesus-Hernandez, M., Mackenzie, I. R., Boeve, B. F., Boxer, A. L., Baker, M., Rutherford, N. J., et al. (2011). Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72, 245-256. doi: 10.1016/j.neuron.2011.09.011
17. deLorimier, E., Coonrod, L. A., Copperman, J., Taber, A., Reister, E. E., Sharma, K., et al. (2014). Modifications to toxic CUG RNAs induce structural stability, rescue mis-splicing in a myotonic dystrophy cell model and reduce toxicity in a myotonic dystrophy zebrafish model. Nucleic Acids Res. 42, 12768-12778. doi: 10.1093/nar/gku941
18. de Mezer, M., Wojciechowska, M., Napierala, M., Sobczak, K., and Krzyzosiak, W. J. (2011). Mutant CAG repeats of Huntingtin transcript fold into hairpins, form nuclear foci and are targets for RNA interference. Nucleic Acids Res. 39, 3852-3863. doi: 10.1093/nar/gkq1323
19. Denli, A. M., Tops, B. B. J., Plasterk, R. H. A., Ketting, R. F., and Hannon, G. J. (2004). Processing of primary microRNAs by the microprocessor complex. Nature 432, 231-235. doi: 10.1038/nature03049
20. Disney, M. D., Liu, B., Yang, W.-Y., Sellier, C., Tran, T., Charlet-Berguerand, N., et al. (2012). A small molecule that targets r(CGG)exp and improves defects in fragile X-associated tremor ataxia syndrome. ACS Chem. Biol. 7, 1711-1718. doi: 10.1021/cb300135h
21. Dodd, D. W., Tomchick, D. R., Corey, D. R., and Gagnon, K. T. (2016). Pathogenic C9ORF72 antisense repeat RNA forms a double helix with tandem C:C mismatches. Biochemistry 55, 1283-1286. doi: 10.1021/acs.biochem.6b00136
22. Dombrowski, C., Lévesque, S., Morel, M. L., Rouillard, P., Morgan, K., and Rousseau, F. (2002). Premutation and intermediate-size FMR1 alleles in 10572 males from the general population: loss of an AGG interruption is a late event in the generation of fragile X syndrome alleles. Hum. Mol. Genet. 11, 371-378. doi: 10.1093/hmg/11.4.371
23. Edwards, J. M., Long, J., de Moor, C. H., Emsley, J., and Searle, M. S. (2013). Structural insights into the targeting of mRNA GU-rich elements by the three RRMs of CELF1. Nucleic Acids Res. 41, 7153-7166. doi: 10.1093/nar/gkt470
24. Eichler, E. E., Holden, J. J. A., Popovich, B. W., Reiss, A. L., Snow, K., Thibodeau, S. N., et al. (1994). Length of uninterrupted CGG repeats determines instability in the FMR1 gene. Nat. Genet. 8, 88-94. doi: 10.1038/ng0994-88
25. Ellegren, H. (2004). Microsatellites: simple sequences with complex evolution. Nat. Rev. Genet. 5, 435-445. doi: 10.1038/nrg1348
26. Fratta, P., Mizielinska, S., Nicoll, A. J., Zloh, M., Fisher, E. M. C., Parkinson, G., et al. (2012). C9orf72 hexanucleotide repeat associated with amyotrophic lateral sclerosis and frontotemporal dementia forms RNA G-quadruplexes. Sci. Rep. 2:1016. doi: 10.1038/srep01016
27. Fu, Y., Ramisetty, S. R., Hussain, N., and Baranger, A. M. (2012). MBNL1-RNA recognition: contributions of MBNL1 sequence and RNA conformation. Chembiochem 13, 112-119. doi: 10.1002/cbic.201100487
28. Goers, E. S., Purcell, J., Voelker, R. B., Gates, D. P., and Berglund, J. A. (2010). MBNL1 binds GC motifs embedded in pyrimidines to regulate alternative splicing. Nucleic Acids Res. 38, 2467-2484. doi: 10.1093/nar/gkp1209
29. González, V., and Hurley, L. H. (2010). The C-terminus of nucleolin promotes the formation of the c-MYC G-quadruplex and inhibits c-MYC promoter activity. Biochemistry 49, 9706-9714. doi: 10.1021/bi100509s
30. Grammatikakis, I., Goo, Y.-H., Echeverria, G. V., and Cooper, T. A. (2011). Identification of MBNL1 and MBNL3 domains required for splicing activation and repression. Nucleic Acids Res. 39, 2769-2780. doi: 10.1093/nar/gkq1155
31. Gregory, R. I., Yan, K.-P., Amuthan, G., Chendrimada, T., Doratotaj, B., Cooch, N., et al. (2004). The microprocessor complex mediates the genesis of microRNAs. Nature 432, 235-240. doi: 10.1038/nature03120
32. Gudanis, D., Popenda, L., Szpotkowski, K., Kierzek, R., and Gdaniec, Z. (2016). Structural characterization of a dimer of RNA duplexes composed of 8-bromoguanosine modified CGG trinucleotide repeats: a novel architecture of RNA quadruplexes. Nucleic Acids Res. 44, 2409-2416. doi: 10.1093/nar/gkv1534
33. Guo, J. U., and Bartel, D. P. (2016). RNA G-quadruplexes are globally unfolded in eukaryotic cells and depleted in bacteria. Science 353:aaf5371. doi: 10.1126/science.aaf5371
34. Haeusler, A. R., Donnelly, C. J., Periz, G., Simko, E. A. J., Shaw, P. G., Kim, M.-S., et al. (2014). C9orf72 nucleotide repeat structures initiate molecular cascades of disease. Nature 507, 195-200. doi: 10.1038/nature13124
35. Hafner, M., Landthaler, M., Burger, L., Khorshid, M., Hausser, J., Berninger, P., et al. (2010). Transcriptome-wide identification of RNA-binding protein and microRNA target sites by PAR-CLIP. Cell 141, 129-141. doi: 10.1016/j.cell.2010.03.009
36. Hagerman, P. (2013). Fragile X-associated tremor/ataxia syndrome (FXTAS): pathology and mechanisms. Acta Neuropathol. 126, 1-19. doi: 10.1007/s00401-013-1138-1
37. Hagerman, R., and Hagerman, P. (2013). Advances in clinical and molecular understanding of the FMR1 premutation and fragile X-associated tremor/ataxia syndrome. Lancet Neurol. 12, 786-798. doi: 10.1016/S1474-4422(13)70125-X
38. Han, J., Lee, Y., Yeom, K.-H., Kim, Y.-K., Jin, H., and Kim, V. N. (2004). The Drosha-DGCR8 complex in primary microRNA processing. Genes Dev. 18, 3016-3027. doi: 10.1101/gad.1262504
39. Han, J., Lee, Y., Yeom, K.-H., Nam, J.-W., Heo, I., Rhee, J.-K., et al. (2006). Molecular basis for the recognition of primary microRNAs by the Drosha-DGCR8 complex. Cell 125, 887-901. doi: 10.1016/j.cell.2006.03.043
40. Handa, V., Saha, T., and Usdin, K. (2003). The fragile X syndrome repeats form RNA hairpins that do not activate the interferon-inducible protein kinase, PKR, but are cut by Dicer. Nucleic Acids Res. 31, 6243-6248. doi: 10.1093/nar/gkg818
41. Handa, V., Yeh, H. J. C., McPhie, P., and Usdin, K. (2005). The AUUCU repeats responsible for spinocerebellar ataxia type 10 form unusual RNA hairpins. J. Biol. Chem. 280, 29340-29345. doi: 10.1074/jbc.m503495200
42. Huppertz, I., Attig, J., D’Ambrogio, A., Easton, L. E., Sibley, C. R., Sugimoto, Y., et al. (2014). iCLIP: protein-RNA interactions at nucleotide resolution. Methods 65, 274-287. doi: 10.1016/j.ymeth.2013.10.011
43. Hussey, J., Lockhart, P. J., Seltzer, W., Wszolek, Z. K., Payami, H., Hanson, M., et al. (2002). Accurate determination of ataxin-2 polyglutamine expansion in patients with intermediate-range repeats. Genet. Test. 6, 217-220. doi: 10.1089/109065702761403397
44. Ikeda, Y., Daughters, R. S., and Ranum, L. P. W. (2008). Bidirectional expression of the SCA8 expansion mutation: one mutation, two genes. Cerebellum 7, 150-158. doi: 10.1007/s12311-008-0010-7
45. Jazurek, M., Ciesiolka, A., Starega-Roslan, J., Bilinska, K., and Krzyzosiak, W. J. (2016). Identifying proteins that bind to specific RNAs - focus on simple repeat expansion diseases. Nucleic Acids Res. 44, 9050-9070. doi: 10.1093/nar/gkw803
46. Jensen, K. B., and Darnell, R. B. (2008). CLIP: crosslinking and immunoprecipitation of in vivo RNA targets of RNA-binding proteins. Methods Mol. Biol. 488, 85-98. doi: 10.1007/978-1-60327-475-3_6
47. Jiang, H., Mankodi, A., Swanson, M. S., Moxley, R. T., and Thornton, C. A. (2004). Myotonic dystrophy type 1 is associated with nuclear foci of mutant RNA, sequestration of muscleblind proteins and deregulated alternative splicing in neurons. Hum. Mol. Genet. 13, 3079-3088. doi: 10.1093/hmg/ddh327
48. Khateb, S., Weisman-Shomer, P., Hershco, I., Loeb, L. A., and Fry, M. (2004). Destabilization of tetraplex structures of the fragile X repeat sequence (CGG)n is mediated by homolog-conserved domains in three members of the hnRNP family. Nucleic Acids Res. 32, 4145-4154. doi: 10.1093/nar/gkh745
49. Khateb, S., Weisman-Shomer, P., Hershco-Shani, I., Ludwig, A. L., and Fry, M. (2007). The tetraplex (CGG)n destabilizing proteins hnRNP A2 and CBF-A enhance the in vivo translation of fragile X premutation mRNA. Nucleic Acids Res. 35, 5775-5788. doi: 10.1093/nar/gkm636
50. Kiliszek, A., Kierzek, R., Krzyzosiak, W. J., and Rypniewski, W. (2009). Structural insights into CUG repeats containing the “stretched U-U wobble”: implications for myotonic dystrophy. Nucleic Acids Res. 37, 4149-4156. doi: 10.1093/nar/gkp350
51. Kiliszek, A., Kierzek, R., Krzyzosiak, W. J., and Rypniewski, W. (2010). Atomic resolution structure of CAG RNA repeats: structural insights and implications for the trinucleotide repeat expansion diseases. Nucleic Acids Res. 38, 8370-8376. doi: 10.1093/nar/gkq700
52. Kiliszek, A., Kierzek, R., Krzyzosiak, W. J., and Rypniewski, W. (2011). Crystal structures of CGG RNA repeats with implications for fragile X-associated tremor ataxia syndrome. Nucleic Acids Res. 39, 7308-7315. doi: 10.1093/nar/gkr368
53. Kim, D.-H., Langlois, M.-A., Lee, K.-B., Riggs, A. D., Puymirat, J., and Rossi, J. J. (2005). HnRNP H inhibits nuclear export of mRNA containing expanded CUG repeats and a distal branch point sequence. Nucleic Acids Res. 33, 3866-3874. doi: 10.1093/nar/gki698
54. Kino, Y., Mori, D., Oma, Y., Takeshita, Y., Sasagawa, N., and Ishuira, S. (2004). Muscleblind protein, MBNL1/EXP, binds specifically to CHHG repeats. Hum. Mol. Genet. 13, 495-507. doi: 10.1093/hmg/ddh056
55. Klass, D. M., Scheibe, M., Butter, F., Hogan, G. J., Mann, M., and Brown, P. O. (2013). Quantitative proteomic analysis reveals concurrent RNA-protein interactions and identifies new RNA-binding proteins in Saccharomyces cerevisiae. Genome Res. 23, 1028-1038. doi: 10.1101/gr.153031.112
56. Konieczny, P., Stepniak-Konieczna, E., and Sobczak, K. (2014). MBNL proteins and their target RNAs, interaction and splicing regulation. Nucleic Acids Res. 42, 10873-10887. doi: 10.1093/nar/gku767
57. König, J., Zarnack, K., Rot, G., Curk, T., Kayikci, M., Zupan, B., et al. (2010). iCLIP reveals the function of hnRNP particles in splicing at individual nucleotide resolution. Nat. Struct. Mol. Biol. 17, 909-915. doi: 10.1038/nsmb.1838.
58. Kramer, K., Sachsenberg, T., Beckmann, B. M., Qamar, S., Boon, K.-L., Hentze, M. W., et al. (2014). Photo-cross-linking and high-resolution mass spectrometry for assignment of RNA-binding sites in RNA-binding proteins. Nat. Methods 11, 1064-1070. doi: 10.1038/nmeth.3092
59. Kumar, A., Park, H., Fang, P., Parkesh, R., Guo, M., Nettles, K. W., et al. (2011). Myotonic dystrophy type 1 RNA crystal structures reveal heterogeneous 1 × 1 nucleotide UU internal loop conformations. Biochemistry 50, 9928-9935. doi: 10.1021/bi2013068
60. Kwon, S. C., Nguyen, T. A., Choi, Y.-G., Jo, M. H., Hohng, S., Kim, V. N., et al. (2016). Structure of human DROSHA. Cell 164, 81-90. doi: 10.1016/j.cell.2015.12.019
61. Lambert, N., Robertson, A., Jangi, M., McGeary, S., Sharp, P. A., and Burge, C. B. (2014). RNA bind-n-seq: quantitative assessment of the sequence and structural binding specificity of RNA binding proteins. Mol. Cell 54, 887-900. doi: 10.1016/j.molcel.2014.04.016
62. Licatalosi, D. D., Mele, A., Fak, J. J., Ule, J., Kayikci, M., Chi, S. W., et al. (2008). HITS-CLIP yields genome-wide insights into brain alternative RNA processing. Nature 456, 464-469. doi: 10.1038/nature07488
63. Lu, Z., Zhang, Q. C., Lee, B., Flynn, R. A., Smith, M. A., Robinson, J. T., et al. (2016). RNA duplex map in living cells reveals higher-order transcriptome structure. Cell 165, 1267-1279. doi: 10.1016/j.cell.2016.04.028
64. Malgowska, M., Gudanis, D., Kierzek, R., Wyszko, E., Gabelica, V., and Gdaniec, Z. (2014). Distinctive structural motifs of RNA G-quadruplexes composed of AGG, CGG and UGG trinucleotide repeats. Nucleic Acids Res. 42, 10196-10207. doi: 10.1093/nar/gku710
65. Mankodi, A., Urbinati, C. R., Yuan, Q. P., Moxley, R. T., Sansone, V., Krym, M., et al. (2001). Muscleblind localizes to nuclear foci of aberrant RNA in myotonic dystrophy types 1 and 2. Hum. Mol. Genet. 10, 2165-2170. doi: 10.1093/hmg/10.19.2165
66. Masliah, G., Barraud, P., and Allain, F. H. T. (2013). RNA recognition by double-stranded RNA binding domains: a matter of shape and sequence. Cell. Mol. Life Sci. 70, 1875-1895. doi: 10.1007/s00018-012-1119-x
67. Matsuyama, Z., Izumi, Y., Kameyama, M., Kawakami, H., and Nakamura, S. (1999). The effect of CAT trinucleotide interruptions on the age at onset of spinocerebellar ataxia type 1 (SCA1). J. Med. Genet. 36, 546-548.
68. Michalowski, S., Miller, J. W., Urbinati, C. R., Paliouras, M., Swanson, M. S., and Griffith, J. (1999). Visualization of double-stranded RNAs from the myotonic dystrophy protein kinase gene and interactions with CUG-binding protein. Nucleic Acids Res. 27, 3534-3542. doi: 10.1093/nar/27.17.3534
69. Michlewski, G., and Krzyzosiak, W. J. (2004). Molecular architecture of CAG repeats in human disease related transcripts. J. Mol. Biol. 340, 665-679. doi: 10.1016/j.jmb.2004.05.021
70. Miller, J. W., Urbinati, C. R., Teng-Umnuay, P., Stenberg, M. G., Byrne, B. J., Thornton, C. A., et al. (2000). Recruitment of human muscleblind proteins to (CUG)n expansions associated with myotonic dystrophy. EMBO J. 19, 4439-4448. doi: 10.1093/emboj/19.17.4439
71. Mooers, B. H. M., Logue, J. S., and Berglund, J. A. (2005). The structural basis of myotonic dystrophy from the crystal structure of CUG repeats. Proc. Natl. Acad. Sci. U S A 102, 16626-16631. doi: 10.1073/pnas.0505873102
72. Mori, D., Sasagawa, N., Kino, Y., and Ishiura, S. (2008). Quantitative analysis of CUG-BP1 binding to RNA repeats. J. Biochem. 143, 377-383. doi: 10.1093/jb/mvm230
73. Mori, K., Weng, S.-M., Arzberger, T., May, S., Rentzsch, K., Kremmer, E., et al. (2013). The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science 339, 1335-1338. doi: 10.1126/science.1232927
74. Moseley, M. L., Zu, T., Ikeda, Y., Gao, W., Mosemiller, A. K., Daughters, R. S., et al. (2006). Bidirectional expression of CUG and CAG expansion transcripts and intranuclear polyglutamine inclusions in spinocerebellar ataxia type 8. Nat. Genet. 38, 758-769. doi: 10.1038/ng1827
75. Napierala, M., and Krzyzosiak, W. J. (1997). CUG repeats present in myotonin kinase RNA form metastable “slippery” hairpins. J. Biol. Chem. 272, 31079-31085. doi: 10.1074/jbc.272.49.31079
76. Napierala, M., Michalowski, D., de Mezer, M., and Krzyzosiak, W. J. (2005). Facile FMR1 mRNA structure regulation by interruptions in CGG repeats. Nucleic Acids Res. 33, 451-463. doi: 10.1093/nar/gki186
77. Nelles, D. A., Fang, M. Y., O’Connell, M. R., Xu, J. L., Markmiller, S. J., Doudna, J. A., et al. (2016). Programmable RNA tracking in live cells with CRISPR/Cas9. Cell 165, 488-496. doi: 10.1016/j.cell.2016.02.054
78. Nguyen, T. A., Jo, M. H., Choi, Y.-G., Park, J., Kwon, S. C., Hohng, S., et al. (2015). Functional anatomy of the human microprocessor. Cell 161, 1374-1387. doi: 10.1016/j.cell.2015.05.010
79. O’Connell, M. R., Oakes, B. L., Sternberg, S. H., East-Seletsky, A., Kaplan, M., and Doudna, J. A. (2014). Programmable RNA recognition and cleavage by CRISPR/Cas9. Nature 516, 263-266. doi: 10.1038/nature13769
80. Ofer, N., Weisman-Shomer, P., Shklover, J., and Fry, M. (2009). The quadruplex r(CGG)n destabilizing cationic porphyrin TMPyP4 cooperates with hnRNPs to increase the translation efficiency of fragile X premutation mRNA. Nucleic Acids Res. 37, 2712-2722. doi: 10.1093/nar/gkp130
81. O’Rourke, J. R., and Swanson, M. S. (2009). Mechanisms of RNA-mediated disease. J. Biol. Chem. 284, 7419-7423. doi: 10.1074/jbc.R800025200
82. Orr, H. T., and Zoghbi, H. Y. (2007). Trinucleotide repeat disorders. Annu. Rev. Neurosci. 30, 575-621. doi: 10.1146/annurev.neuro.29.051605.113042
83. Osborne, R. J., and Thornton, C. A. (2006). RNA-dominant diseases. Hum. Mol. Genet. 15, R162-R169. doi: 10.1093/hmg/ddl181
84. Park, H., González, à. L., Yildirim, I., Tran, T., Lohman, J. R., Fang, P., et al. (2015). Crystallographic and computational analyses of AUUCU repeating RNA that causes spinocerebellar ataxia type 10 (SCA10). Biochemistry 54, 3851-3859. doi: 10.1021/acs.biochem.5b00551
85. Pearson, C. E., Eichler, E. E., Lorenzetti, D., Kramer, S. F., Zoghbi, H. Y., Nelson, D. L., et al. (1998). Interruptions in the triplet repeats of SCA1 and FRAXA reduce the propensity and complexity of slipped strand DNA (S-DNA) formation. Biochemistry 37, 2701-2708. doi: 10.1021/bi972546c
86. Peel, A. L., Rao, R. V., Cottrell, B. A., Hayden, M. R., Ellerby, L. M., and Bredesen, D. E. (2001). Double-stranded RNA-dependent protein kinase, PKR, binds preferentially to Huntington’s disease (HD) transcripts and is activated in HD tissue. Hum. Mol. Genet. 10, 1531-1538. doi: 10.1093/hmg/10.15.1531
87. Pinheiro, P., Scarlett, G., Rodger, A., Mark Rodger, P., Murray, A., Brown, T., et al. (2002). Structures of CUG repeats in RNA: potential implications for human genetic diseases. J. Biol. Chem. 277, 35183-35190. doi: 10.1074/jbc.M202235200
88. Purcell, J., Oddo, J. C., Wang, E. T., and Berglund, J. A. (2012). Combinatorial mutagenesis of MBNL1 zinc fingers elucidates distinct classes of regulatory events. Mol. Cell. Biol. 32, 4155-4167. doi: 10.1128/MCB.00274-12
89. Ranum, L. P. W., and Cooper, T. A. (2006). Rna-mediated neuromuscular disorders. Annu. Rev. Neurosci. 29, 259-277. doi: 10.1146/annurev.neuro.29.051605.113014
90. Reddy, K., Zamiri, B., Stanley, S. Y. R., Macgregor, R. B., and Pearson, C. E. (2013). The disease-associated r(GGGGCC)n repeat from the C9orf72 gene forms tract length-dependent uni- and multimolecular RNA G-quadruplex structures. J. Biol. Chem. 288, 9860-9866. doi: 10.1074/jbc.c113.452532
91. Rehman, S., Gladman, J. T., Periasamy, A., Sun, Y., and Mahadevan, M. S. (2014). Development of an AP-FRET based analysis for characterizing RNA-protein interactions in myotonic dystrophy (DM1). PLoS One 9:e95957. doi: 10.1371/journal.pone.0095957
92. Renton, A. E., Majounie, E., Waite, A., Simón-Sánchez, J., Rollinson, S., Gibbs, J. R., et al. (2011). A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72, 257-268. doi: 10.1016/j.neuron.2011.09.010
93. Rossi, S., Serrano, A., Gerbino, V., Giorgi, A., Di Francesco, L., Nencini, M., et al. (2015). Nuclear accumulation of mRNAs underlies G4C2-repeat-induced translational repression in a cellular model of C9orf72 ALS. J. Cell Sci. 128, 1787-1799. doi: 10.1242/jcs.165332
94. Rozanska, M., Sobczak, K., Jasinska, A., Napierala, M., Kaczynska, D., Czerny, A., et al. (2007). CAG and CTG repeat polymorphism in exons of human genes shows distinct features at the expandable loci. Hum. Mutat. 28, 451-458. doi: 10.1002/humu.20466
95. Saunders, L. R., and Barber, G. N. (2003). The dsRNA binding protein family: critical roles, diverse cellular functions. FASEB J. 17, 961-983. doi: 10.1096/fj.02-0958rev
96. Schmidt, C., Kramer, K., and Urlaub, H. (2012). Investigation of protein-RNA interactions by mass spectrometry-Techniques and applications. J. Proteomics 75, 3478-3494. doi: 10.1016/j.jprot.2012.04.030
97. Sellier, C., Freyermuth, F., Tabet, R., Tran, T., He, F., Ruffenach, F., et al. (2013). Sequestration of DROSHA and DGCR8 by expanded CGG RNA repeats alters microRNA processing in fragile X-associated tremor/ataxia syndrome. Cell Rep. 3, 869-880. doi: 10.1016/j.celrep.2013.02.004
98. Sharma, E., Sterne-Weiler, T., O’Hanlon, D., and Blencowe, B. J. (2016). Global mapping of human RNA-RNA interactions. Mol. Cell 62, 618-626. doi: 10.1016/j.molcel.2016.04.030
99. Smith, B. N., Newhouse, S., Shatunov, A., Vance, C., Topp, S., Johnson, L., et al. (2013). The C9ORF72 expansion mutation is a common cause of ALS+/-FTD in Europe and has a single founder. Eur. J. Hum. Genet. 21, 102-108. doi: 10.1038/ejhg.2012.98
100. Sobczak, K., de Mezer, M., Michlewski, G., Krol, J., and Krzyzosiak, W. J. (2003). RNA structure of trinucleotide repeats associated with human neurological diseases. Nucleic Acids Res. 31, 5469-5482. doi: 10.1093/nar/gkg766
101. Sobczak, K., and Krzyzosiak, W. J. (2004a). Imperfect CAG repeats form diverse structures in SCA1 transcripts. J. Biol. Chem. 279, 41563-41572. doi: 10.1074/jbc.m405130200
102. Sobczak, K., and Krzyzosiak, W. J. (2004b). Patterns of CAG repeat interruptions in SCA1 and SCA2 genes in relation to repeat instability. Hum. Mutat. 24, 236-247. doi: 10.1002/humu.20075
103. Sobczak, K., and Krzyzosiak, W. J. (2005). CAG repeats containing CAA interruptions form branched hairpin structures in spinocerebellar ataxia type 2 transcripts. J. Biol. Chem. 280, 3898-3910. doi: 10.1074/jbc.m409984200
104. Sobczak, K., Michlewski, G., de Mezer, M., Kierzek, E., Krol, J., Olejniczak, M., et al. (2010). Structural diversity of triplet repeat RNAs. J. Biol. Chem. 285, 12755-12764. doi: 10.1074/jbc.M109.078790
105. Starega-Roslan, J., Witkos, T. M., Galka-Marciniak, P., and Krzyzosiak, W. J. (2015). Sequence features of Drosha and Dicer cleavage sites affect the complexity of isomiRs. Int. J. Mol. Sci. 16, 8110-8127. doi: 10.3390/ijms16048110
106. Sun, X., Li, P. P., Zhu, S., Cohen, R., Marque, L. O., Ross, C. A., et al. (2015). Nuclear retention of full-length HTT RNA is mediated by splicing factors MBNL1 and U2AF65. Sci. Rep. 5:12521. doi: 10.1038/srep12521
107. Sznajder, Ł. J., Michalak, M., Taylor, K., Cywoniuk, P., Kabza, M., Wojtkowiak-Szlachcic, A., et al. (2016). Mechanistic determinants of MBNL activity. Nucleic Acids Res. 44, 10326-10342. doi: 10.1093/nar/gkw915
108. Takahashi, N., Sasagawa, N., Suzuki, K., and Ishiura, S. (2000). The CUG-binding protein binds specifically to UG dinucleotide repeats in a yeast three-hybrid system. Biochem. Biophys. Res. Commun. 277, 518-523. doi: 10.1006/bbrc.2000.3694
109. Tamjar, J., Katorcha, E., Popov, A., and Malinina, L. (2012). Structural dynamics of double-helical RNAs composed of CUG/CUG- and CUG/CGG-repeats. J. Biomol. Struct. Dyn. 30, 505-523. doi: 10.1080/07391102.2012.687517
110. Tawani, A., and Kumar, A. (2015). Structural insights reveal the dynamics of the repeating r(CAG) transcript found in Huntington’s disease (HD) and spinocerebellar ataxias (SCAs). PLoS One 10:e0131788. doi: 10.1371/journal.pone.0131788
111. Teplova, M., and Patel, D. J. (2008). Structural insights into RNA recognition by the alternative- splicing regulator muscleblind-like MBNL1. Nat. Struct. Mol. Biol. 15, 1343-1351. doi: 10.1038/nsmb.1519
112. Thornton, C. A. (2014). Myotonic dystrophy. Neurol. Clin. 32, 705-719. doi: 10.1016/j.ncl.2014.04.011
113. Tian, B., Bevilacqua, P. C., Diegelman-Parente, A., and Mathews, M. B. (2004). The double-stranded-RNA-binding motif: interference and much more. Nat. Rev. Mol. Cell Biol. 5, 1013-1023. doi: 10.1038/nrm1528
114. Tian, B., White, R. J., Xia, T., Welle, S., Turner, D. H., Mathews, M. B., et al. (2000). Expanded CUG repeat RNAs form hairpins that activate the double-stranded RNA-dependent protein kinase PKR. RNA 6, 79-87. doi: 10.1017/s1355838200991544
115. Timchenko, N. A., Welm, A. L., Lu, X., and Timchenko, L. T. (1999). CUG repeat binding protein (CUGBP1) interacts with 5′ region of C/EBPβ mRNA and regulates translation of C/EBPβ isoforms. Nucleic Acids Res. 27, 4517-4525. doi: 10.1093/nar/27.22.4517
116. Timchenko, L. T., Miller, J. W., Timchenko, N. A., Devore, D. R., Datar, K. V., Lin, L., et al. (1996a). Identification of a (CUG)n triplet repeat RNA-binding protein and its expression in myotonic dystrophy. Nucleic Acids Res. 24, 4407-4414. doi: 10.1093/nar/24.22.4407
117. Timchenko, L. T., Timchenko, N. A., Caskey, C. T., and Roberts, R. (1996b). Novel proteins with binding specificity for DNA CTG repeats and RNA CUG repeats: implications for myotonic dystrophy. Hum. Mol. Genet. 5, 115-121. doi: 10.1093/hmg/5.1.115
118. Todd, P. K., Oh, S.-Y., Krans, A., He, F., Sellier, C., Frazer, M., et al. (2013). CGG repeat-associated translation mediates neurodegeneration in fragile X tremor ataxia syndrome. Neuron 78, 440-455. doi: 10.1016/j.neuron.2013.03.026
119. Tran, T., Childs-Disney, J. L., Liu, B., Guan, L., Rzuczek, S., and Disney, M. D. (2014). Targeting the r(CGG) repeats that cause FXTAS with modularly assembled small molecules and oligonucleotides. ACS Chem. Biol. 9, 904-912. doi: 10.1021/cb400875u
120. Tsai, B. P., Wang, X., Huang, L., and Waterman, M. L. (2011). Quantitative profiling of in vivo-assembled RNA-protein complexes using a novel integrated proteomic approach. Mol. Cell. Proteomics 10:M110.007385. doi: 10.1074/mcp.M110.007385
121. Tsoi, H., Lau, C. K., Lau, K. F., and Chan, H. Y. E. (2011). Perturbation of U2AF65/NXF1-mediated RNA nuclear export enhances RNA toxicity in polyQ diseases. Hum. Mol. Genet. 20, 3787-3797. doi: 10.1093/hmg/ddr297
122. Tsoi, H., Lau, T. C.-K., Tsang, S.-Y., Lau, K.-F., and Chan, H. Y. E. (2012). CAG expansion induces nucleolar stress in polyglutamine diseases. Proc. Natl. Acad. Sci. U S A 109, 13428-13433. doi: 10.1073/pnas.1204089109
123. Tsuda, K., Kuwasako, K., Takahashi, M., Someya, T., Inoue, M., Terada, T., et al. (2009). Structural basis for the sequence-specific RNA-recognition mechanism of human CUG-BP1 RRM3. Nucleic Acids Res. 37, 5151-5166. doi: 10.1093/nar/gkp546
124. Ule, J., Jensen, K., Mele, A., and Darnell, R. B. (2005). CLIP: a method for identifying protein-RNA interaction sites in living cells. Methods 37, 376-386. doi: 10.1016/j.ymeth.2005.07.018
125. Van Nostrand, E. L., Pratt, G. A., Shishkin, A. A., Gelboin-Burkhart, C., Fang, M. Y., Sundararaman, B., et al. (2016). Robust transcriptome-wide discovery of RNA-binding protein binding sites with enhanced CLIP (eCLIP). Nat. Methods 13, 508-514. doi: 10.1038/nmeth.3810
126. Wang, E. T., Cody, N. A. L., Jog, S., Biancolella, M., Wang, T. T., Treacy, D. J., et al. (2012). Transcriptome-wide regulation of pre-mRNA splicing and mRNA localization by muscleblind proteins. Cell 150, 710-724. doi: 10.1016/j.cell.2012.06.041
127. Warf, M. B., and Berglund, J. A. (2007). MBNL binds similar RNA structures in the CUG repeats of myotonic dystrophy and its pre-mRNA substrate cardiac troponin T. RNA 13, 2238-2251. doi: 10.1261/rna.610607
128. Wojciechowska, M., Olejniczak, M., Galka-Marciniak, P., Jazurek, M., and Krzyzosiak, W. J. (2014). RAN translation and frameshifting as translational challenges at simple repeats of human neurodegenerative disorders. Nucleic Acids Res. 42, 11849-11864. doi: 10.1093/nar/gku794
129. Yang, W.-Y., He, F., Strack, R. L., Oh, S. Y., Frazer, M., Jaffrey, S. R., et al. (2016). Small molecule recognition and tools to study modulation of r(CGG)exp in fragile x-associated tremor ataxia syndrome. ACS Chem. Biol. 11, 2456-2465. doi: 10.1021/acschembio.6b00147
130. Yildirim, I., Park, H., Disney, M. D., and Schatz, G. C. (2013). A dynamic structural model of expanded RNA CAG repeats: a refined X-ray structure and computational investigations using molecular dynamics and umbrella sampling simulations. J. Am. Chem. Soc. 135, 3528-3538. doi: 10.1021/ja3108627
131. Yuan, Y., Compton, S. A., Sobczak, K., Stenberg, M. G., Thornton, C. A., Griffith, J. D., et al. (2007). Muscleblind-like 1 interacts with RNA hairpins in splicing target and pathogenic RNAs. Nucleic Acids Res. 35, 5474-5486. doi: 10.1093/nar/gkm601
132. Zamiri, B., Reddy, K., Macgregor, R. B. Jr., and Pearson, C. E. (2014). TMPyP4 porphyrin distorts RNA G-quadruplex structures of the disease-associated r(GGGGCC)n repeat of the C9orf72 gene and blocks interaction of RNA-binding proteins. J. Biol. Chem. 289, 4653-4659. doi: 10.1074/jbc.C113.502336
133. Zhang, C., and Darnell, R. B. (2011). Mapping in vivo protein-RNA interactions at single-nucleotide resolution from HITS-CLIP data. Nat. Biotechnol. 29, 607-614. doi: 10.1038/nbt.1873
134. Zhang, K., Donnelly, C. J., Haeusler, A. R., Grima, J. C., Machamer, J. B., Steinwald, P., et al. (2015). The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature 525, 56-61. doi: 10.1038/nature14973
135. Zu, T., Gibbens, B., Doty, N. S., Gomes-Pereira, M., Huguet, A., Stone, M. D., et al. (2011). Non-ATG-initiated translation directed by microsatellite expansions. Proc. Natl. Acad. Sci. U S A 108, 260-265. doi: 10.1073/pnas.1013343108
136. Zumwalt, M., Ludwig, A., Hagerman, P. J., and Dieckmann, T. (2007). Secondary structure and dynamics of the r(CGG) repeat in the mRNA of the fragile X mental retardation 1(FMR1) gene. RNA Biol. 4, 93-100. doi: 10.4161/rna.4.2.5039