Genomics & Informatics

Korea Genome Organization (한국유전체학회)
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RNA Mapping of Mutant Myotonic Dystrophy Protein Kinase 3'-Untranslated Region Transcripts

  • Song, Min-Sun (Department of Molecular Biology, BK21 Graduate Program for RNA Biology, Institute of Nanosensor and Biotechnology, Dankook University) ;
  • Lee, Seong-Wook (Department of Molecular Biology, BK21 Graduate Program for RNA Biology, Institute of Nanosensor and Biotechnology, Dankook University)
  • Published : 2009.12.31
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Abstract

Myotonic dystrophy type 1 (DM1), which is a dominantly inherited neurodegenerative disorder, results from a CTG trinucleotide repeat expansion in the 3'-untranslated region (3'-UTR) of the myotonic dystrophy protein kinase (DMPK) gene. Retention of mutant DMPK (mDMPK) transcripts in the nuclei of affected cells has been known to be the main cause of pathogenesis of the disease. Thus, reducing the RNA toxicity through elimination of the mutant RNA has been suggested as one therapeutic strategy against DM1. In this study, we suggested RNA replacement with a trans -splicing ribozyme as an alternate genetic therapeutic approach for amelioration of DM1. To this end, we identified the regions of mDMPK 3'-UTR RNA that were accessible to ribozymes by using an RNA mapping strategy based on a trans-splicing ribozyme library. We found that particularly accessible sites were present not only upstream but also downstream of the expanded repeat sequence. Repair or replacement of the mDMPK transcript with the specific ribozyme will be useful for DM1 treatment through reduction of toxic mutant transcripts and simultaneously restore wild-type DMPK or release nucleus-entrapped mDMPK transcripts to the cytoplasm.

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References

  1. Been, M., and Cech, T. (1986). One binding site determines sequence specificity of Tetrahymena pre-rRNA self-splicing, trans-splicing, and RNA enzyme activity. Cell 47, 207-216 https://doi.org/10.1016/0092-8674(86)90443-5
  2. Brook, J.D., McCurrach, M.E., Harley, H.G., Buckler, A.J., Church, D., Aburatani, H., Hunter, K., Stanton, V.P., Thirion, J.P., Hudson, T., Sohn, R., Zemelman, B., Snell, R.G., Rundle, S.A., Crow, S., Davies, J., Shelbourne, P., Buxton, J., Jones, C., Juvonen, V., Johnson, K., Harper, P.S., Shaw, D.J., and Housman, D.J. (1992). Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3'end of a transcript encoding a protein kinase family member. Cell 68, 799-808 https://doi.org/10.1016/0092-8674(92)90154-5
  3. Furling, D., Doucet, G., Langlois, M.A., Timchenko, L., Belanger, E., Cossette, L., and Puymirat, J. (2003). Viral vector producing antisense RNA restores myotonic dystrophy myoblast functions. Gene Ther. 10, 795-802 https://doi.org/10.1038/sj.gt.3301955
  4. Harper, P.S. (2001). Myotinic dystrophy. 3rd ed. London: W.B. Saunders
  5. Hong, S.H., Jeong, J.S., Lee, Y.J., Jung, H.I., Cho, K.S., Kim, C.M., Kwon, B.S., Sullenger, B.A., Lee, S.W., and Kim, I.H. (2008). In vivo reprogramming of hTERT by trans-splicing ribozyme to target tumor cell. Mol. Ther. 16, 74-80 https://doi.org/10.1038/sj.mt.6300282
  6. Jeong, J.S., Lee, S.W., Hong, S.H., Lee, Y.J., Jung, H.I., Cho, K.S., Seo, H.H., Lee, S.J., Park, S., Song, M.S., Kim, C.M., and Kim, I.H. (2008). Antitumor effects of systemically delivered adenovirus harboring trans -splicing ribozyme in intrahepatic colon cancer mouse model. Clin. Cancer Res. 14, 281-290 https://doi.org/10.1158/1078-0432.CCR-07-1524
  7. Jones, J.T., Lee, S.W., and Sullenger, B.A. (1996). Tagging ribozyme reaction sites to follow trans -splicing in mammalian cells. Nature Med. 2, 643-648 https://doi.org/10.1038/nm0696-643
  8. Kaliman, P., and Llagostera, P. (2008). Myotonic dystrophy protein kinase (DMPK) and its role in the pathogenesis of myotonic dystrophy 1. Cell. Signal. 20, 1935-1941 https://doi.org/10.1016/j.cellsig.2008.05.005
  9. Krol, J., Fiszer, A., Mykowska, A., Sobczak, K., de Mezer, M., and Krzyzosiak, W.J. (2007). Ribonuclease dicer cleaves triplet repeat hairpins into shorter repeats that silence specific targets. Mol. Cell. 25, 575-586 https://doi.org/10.1016/j.molcel.2007.01.031
  10. Kwon, B.S., Jung, H.S., Song, M.S., Cho, K.S., Kim, S.C., Kimm, K., Jeong, J.S., Kim, I.H., and Lee, S.W. (2005). Specific regression of human cancer cells by ribozymemediated targeted replacement of tumor-specific transcript. Mol. Ther. 12, 824-834 https://doi.org/10.1016/j.ymthe.2005.06.096
  11. Lan, N., Howrey, R.P., Lee, S.W., Smith, C.A., and Sullenger, B.A. (1998). Ribozyme-mediated repair of sickle $\beta$-globin mRNAs in erythrocyte precursors. Science 280, 1593-1596 https://doi.org/10.1126/science.280.5369.1593
  12. Lan, N., Rooney, B.L., Lee, S.W., Howrey, R.P., Smith, C.A., and Sullenger, B.A. (2000). Enhancing RNA repair efficiency by combining trans -splicing ribozymes that recognize different accessible sites on a target RNA. Mol. Ther. 2, 245-255 https://doi.org/10.1006/mthe.2000.0125
  13. Langlois, M.A., Lee, N.S., Rossi, J.J., and Puymirat, J. (2003). Hammerhead ribozyme-mediated destruction of nuclear foci in myotonic dystrophy myoblasts. Mol. Ther. 7, 670-680 https://doi.org/10.1016/S1525-0016(03)00068-6
  14. Long, M.B., Jones, J.P. 3rd, Sullenger, B.A., and Byun, J. (2003). Ribozyme-mediated revision of RNA and DNA. J. Clin. Invest. 112, 312-318 https://doi.org/10.1172/JCI19386
  15. Mahadevan, M.S., Yadava, R.S., Yu, Q., Balijepalli, S., Frenzel-McCardell, C.D., Bourne, T.D., and Phillips, L.H. (2006). Reversible model of RNA toxicity and cardiac conduction defects in myotonic dystrophy. Nat. Genet. 38, 1066-1070 https://doi.org/10.1038/ng1857
  16. Mastroyiannopoulos, N.P., Chrysanthou, E., Kyriakides, T.C., Uney, J.B., Mahadevan, M.S., and Phylactou, L.A. (2008). The effect of myotonic dystrophy transcript levels and location on muscle differentiation. Biochem Biophys . Res. Commun. 377, 526-531 https://doi.org/10.1016/j.bbrc.2008.10.031
  17. Mastroyiannopoulos, N.P., Feldman, M.L., Uney, J.B., Mahadevan, M.S., and Leonidas A.P. (2005). Woodchuck post-transcriptional element induces nuclear export of myotonic dystrophy 3’ untranslated region transcripts. EMBO Rep. 6, 458-463 https://doi.org/10.1038/sj.embor.7400390
  18. Phylactou, L.A., Darrah, C., and Wood, M.A.J. (1998). Ribozyme-mediated trans -splicing of a trinucleotide repeat. Nat. Genet. 18, 378-381 https://doi.org/10.1038/ng0498-378
  19. Rogers, C.S., Vanoye, C.G., Sullenger, B.A., and George, A.L. (2002). Functional repair of a mutant chloride channel using a trans -splicing ribozyme. J. Clin. Invest. 110, 1783-1798 https://doi.org/10.1172/JCI200216481
  20. Ryu, K.J., and Lee, S.W. (2004). Comparative analysis of intracellular trans -splicing ribozyme activity against hepatitis C virus internal ribosome entry site. J. Microbiol. 42, 361-364
  21. Ryu, K.J., Kim, J.H., and Lee, S.W. (2003). Ribozyme-mediated selective induction of new gene activity in hepatitis C virus internal ribosome entry site-expressing cells by targeted trans -splicing. Mol. Ther. 7, 386-395 https://doi.org/10.1016/S1525-0016(02)00063-1
  22. Song, M.S., and Lee, S.W. (2007). An RNA mapping strategy to identify ribozyme-accessible sites on the catalytic subunit of mouse telomerase. Genom. Inform. 5, 32-35
  23. Song, M.S., and Lee, S.W. (2008). In vivo target RNA specificity of trans -splicing phenomena by the group I intron. Genom. Inform. 6, 84-86 https://doi.org/10.5808/GI.2008.6.2.084
  24. Song, M.S., Jeong, J.S., Ban, G. Lee, J.H., Won, Y.S., Cho, K.S., Kim, I.H., and Lee, S.W. (2009). Validation of tissue-specific promoter-driven tumor-targeting trans-splicing ribozyme system as a multifunctional cancer gene therapy device in vivo . Cancer Gene Ther. 16, 113-125 https://doi.org/10.1038/cgt.2008.64
  25. Sullenger, B.A. (1995). Revising messages traveling along the cellular information highway. Chem. Biol. 2, 249-253 https://doi.org/10.1016/1074-5521(95)90043-8
  26. Sullenger, B.A., and Cech, T.R. (1994). Ribozyme-mediated repair of defective mRNA by targeted trans -splicing. Nature 317, 619-622
  27. Sullenger, B.A., and Gilboa, E. (2002). Emerging clinical applications of RNA. Nature 418, 252-258 https://doi.org/10.1038/418252a
  28. Wheeler, T.M. (2008). Myotonic dystrophy: therapeutic strategies for the future. Neurotherapeutics 5, 592-600 https://doi.org/10.1016/j.nurt.2008.08.001
  29. Zuker, M. (2003). Mfold web server for nucleic acid folding and hybridization prediction. Nucl. Acids Res. 31, 3406-3415 https://doi.org/10.1093/nar/gkg595