Skip to main content

Beyond DNA: Zinc Finger Domains as RNA-Binding Modules

  • Protocol
  • First Online:
Engineered Zinc Finger Proteins

Part of the book series: Methods in Molecular Biology ((MIMB,volume 649))

Abstract

Over the last 25 years, we have learned that many structural classes of zinc-binding domains (zinc fingers, ZFs) exist and it has become clear that the molecular functions of these domains are by no means limited to the sequence-specific recognition of double-stranded DNA. For example, ZFs can act as protein recognition or RNA-binding modules, and some domains can exhibit more than one function. In this chapter we describe the progress that has been made in understanding the role of ZF domains as RNA-recognition modules, and we speculate about both the prevalence of such functions and the prospects for creating designer ZFs that target RNA.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Miller, J., McLachlan, A.D., and Klug, A. (1985) Repetitive zinc-binding domains in the protein transcription factor IIIA from Xenopus oocytes. EMBO J. 4, 1609–1614.

    PubMed  CAS  Google Scholar 

  2. Pavletich, N.P. and Pabo, C.O. (1991) Zinc finger-DNA recognition: crystal structure of a Zif268-DNA complex at 2.1 A. Science. 252, 809–817.

    Article  PubMed  CAS  Google Scholar 

  3. Segal, D.J. and Barbas, C.F., 3rd (2001) Custom DNA-binding proteins come of age: polydactyl zinc-finger proteins. Curr Opin Biotechnol. 12, 632–637.

    Article  PubMed  CAS  Google Scholar 

  4. Omichinski, J.G., Pedone, P.V., Felsenfeld, G., Gronenborn, A.M., and Clore, G.M. (1997) The solution structure of a specific GAGA factor-DNA complex reveals a modular binding mode. Nat Struct Biol. 4, 122–132.

    Article  PubMed  CAS  Google Scholar 

  5. Mackay, J.P. and Crossley, M. (1998) Zinc fingers are sticking together. Trends Biochem. Sci.. 23, 1–4.

    Article  PubMed  CAS  Google Scholar 

  6. Zang, W.Q. and Romaniuk, P.J. (1995) Characterization of the 5 S RNA binding activity of Xenopus zinc finger protein p43. J Mol Biol. 245, 549–558.

    Article  PubMed  CAS  Google Scholar 

  7. Zang, W.Q., Veldhoen, N., and Romaniuk, P.J. (1995) Effects of zinc finger mutations on the nucleic acid binding activities of Xenopus transcription factor IIIA. Biochemistry. 34, 15545–15552.

    Article  PubMed  CAS  Google Scholar 

  8. Lu, D., Searles, M.A., and Klug, A. (2003) Crystal structure of a zinc-finger-RNA complex reveals two modes of molecular recognition. Nature. 426, 96–100.

    Article  PubMed  CAS  Google Scholar 

  9. Pelham, H.R. and Brown, D.D. (1980) A specific transcription factor that can bind either the 5S RNA gene or 5S RNA. Proc Natl Acad Sci USA. 77, 4170–4174.

    Article  PubMed  CAS  Google Scholar 

  10. Nolte, R.T., Conlin, R.M., Harrison, S.C., and Brown, R.S. (1998) Differing roles for zinc fingers in DNA recognition: structure of a six-finger transcription factor IIIA complex. Proc Natl Acad Sci USA. 95, 2938–2943.

    Article  PubMed  CAS  Google Scholar 

  11. Joho, K.E., Darby, M.K., Crawford, E.T., and Brown, D.D. (1990) A finger protein structurally similar to TFIIIA that binds exclusively to 5S RNA in Xenopus. Cell. 61, 293–300.

    Article  PubMed  CAS  Google Scholar 

  12. Pritchard-Jones, K., Fleming, S., Davidson, D., Bickmore, W., Porteous, D., Gosden, C., Bard, J., Buckler, A., Pelletier, J., Housman, D., et al (1990) The candidate Wilms’ tumour gene is involved in genitourinary development. Nature. 346, 194–197.

    Article  PubMed  CAS  Google Scholar 

  13. Hastie, N.D. (2001) Life, sex, and WT1 isoforms – three amino acids can make all the difference. Cell. 106, 391–394.

    Article  PubMed  CAS  Google Scholar 

  14. Stoll, R., Lee, B.M., Debler, E.W., Laity, J.H., Wilson, I.A., Dyson, H.J., and Wright, P.E. (2007) Structure of the Wilms tumor suppressor protein zinc finger domain bound to DNA. J Mol Biol. 372, 1227–1245.

    Article  PubMed  CAS  Google Scholar 

  15. Caricasole, A., Duarte, A., Larsson, S.H., Hastie, N.D., Little, M., Holmes, G., Todorov, I., and Ward, A. (1996) RNA binding by the Wilms tumor suppressor zinc finger proteins. Proc Natl Acad Sci USA. 93, 7562–7566.

    Article  PubMed  CAS  Google Scholar 

  16. Morrison, A.A., Venables, J.P., Dellaire, G., and Ladomery, M.R. (2006) The Wilms tumour suppressor protein WT1 (+KTS isoform) binds alpha-actinin 1 mRNA via its zinc-finger domain. Biochem Cell Biol. 84, 789–798.

    Article  PubMed  CAS  Google Scholar 

  17. Bardeesy, N. and Pelletier, J. (1998) Overlapping RNA and DNA binding domains of the wt1 tumor suppressor gene product. Nucleic Acids Res. 26, 1784–1792.

    Article  PubMed  CAS  Google Scholar 

  18. Zhai, G., Iskandar, M., Barilla, K., and Romaniuk, P.J. (2001) Characterization of RNA aptamer binding by the Wilms’ tumor suppressor protein WT1. Biochemistry. 40, 2032–2040.

    Article  PubMed  CAS  Google Scholar 

  19. Bradford, S.T., Wilhelm, D., Bandiera, R., Vidal, V., Schedl, A., and Koopman, P. (2009) A cell-autonomous role for WT1 in regulating Sry in vivo. Hum Mol Genet. 18, 3429–3438.

    Article  PubMed  CAS  Google Scholar 

  20. Larsson, S.H., Charlieu, J.P., Miyagawa, K., Engelkamp, D., Rassoulzadegan, M., Ross, A., Cuzin, F., van Heyningen, V., and Hastie, N.D. (1995) Subnuclear localization of WT1 in splicing or transcription factor domains is regulated by alternative splicing. Cell. 81, 391–401.

    Article  PubMed  CAS  Google Scholar 

  21. Weiss, T.C. and Romaniuk, P.J. (2009) Contribution of individual amino acids to the RNA binding activity of the Wilms’ tumor suppressor protein WT1. Biochemistry. 48, 148–155.

    Article  PubMed  CAS  Google Scholar 

  22. Andreeva, A. and Tidow, H. (2008) A novel CHHC Zn-finger domain found in spliceosomal proteins and tRNA modifying enzymes. Bioinformatics. 24, 2277–2280.

    Article  PubMed  CAS  Google Scholar 

  23. Burge, C.B., Padgett, R.A., and Sharp, P.A. (1998) Evolutionary fates and origins of U12-type introns. Mol Cell. 2, 773–785.

    Article  PubMed  CAS  Google Scholar 

  24. Tidow, H., Andreeva, A., Rutherford, T.J., and Fersht, A.R. (2009) Solution structure of the U11-48 K CHHC zinc-finger domain that specifically binds the 5′ splice site of U12-type introns. Structure. 17, 294–302.

    Article  PubMed  CAS  Google Scholar 

  25. Finerty, P.J., Jr. and Bass, B.L. (1997) A Xenopus zinc finger protein that specifically binds dsRNA and RNA-DNA hybrids. J Mol Biol. 271, 195–208.

    Article  PubMed  CAS  Google Scholar 

  26. Shi, Y. and Berg, J.M. (1995) Specific DNA-RNA hybrid binding by zinc finger proteins. Science. 268, 282–284.

    Article  PubMed  CAS  Google Scholar 

  27. Varmeh-Ziaie, S., Okan, I., Wang, Y., Magnusson, K.P., Warthoe, P., Strauss, M., and Wiman, K.G. (1997) Wig-1, a new p53-induced gene encoding a zinc finger protein. Oncogene. 15, 2699–2704.

    Article  PubMed  CAS  Google Scholar 

  28. Yang, M., May, W.S., and Ito, T. (1999) JAZ requires the double-stranded RNA-binding zinc finger motifs for nuclear localization. J Biol Chem. 274, 27399–27406.

    Article  PubMed  CAS  Google Scholar 

  29. Higashi, Y., Asanuma, M., Miyazaki, I., Haque, M.E., Fujita, N., Tanaka, K., and Ogawa, N. (2002) The p53-activated gene, PAG608, requires a zinc finger domain for nuclear localization and oxidative stress-induced apoptosis. J Biol Chem. 277, 42224–42232.

    Article  PubMed  CAS  Google Scholar 

  30. Yang, M., Wu, S., Su, X., and May, W.S. (2006) JAZ mediates G1 cell-cycle arrest and apoptosis by positively regulating p53 transcriptional activity. Blood. 108, 4136–4145.

    Article  PubMed  CAS  Google Scholar 

  31. Moller, H.M., Martinez-Yamout, M.A., Dyson, H.J., and Wright, P.E. (2005) Solution structure of the N-terminal zinc fingers of the Xenopus laevis double-stranded RNA-binding protein ZFa. J Mol Biol. 351, 718–730.

    Article  PubMed  Google Scholar 

  32. Andreeva, A. and Murzin, A.G. (2008) A fortuitous insight into a common mode of RNA recognition by the dsRNA-specific zinc fingers. Proc Natl Acad Sci USA. 105, E.

    Article  Google Scholar 

  33. Zhou, C. and Huang, R.H. (2008) Crystallographic snapshots of eukaryotic dimethylallyltransferase acting on tRNA: insight into tRNA recognition and reaction mechanism. Proc Natl Acad Sci USA. 105, 16142–16147.

    Article  PubMed  CAS  Google Scholar 

  34. Du, H. and Rosbash, M. (2002) The U1 snRNP protein U1C recognizes the 5′ splice site in the absence of base pairing. Nature. 419, 86–90.

    Article  PubMed  CAS  Google Scholar 

  35. Muto, Y., Pomeranz Krummel, D., Oubridge, C., Hernandez, H., Robinson, C.V., Neuhaus, D., and Nagai, K. (2004) The structure and biochemical properties of the human spliceosomal protein U1C. J Mol Biol. 341, 185–198.

    Article  PubMed  CAS  Google Scholar 

  36. Zeitz, M.J., Malyavantham, K.S., Seifert, B., and Berezney, R. (2009) Matrin 3: Chromosomal distribution and protein interactions. J Cell Biochem. 108, 125–133.

    Article  PubMed  CAS  Google Scholar 

  37. Amarasinghe, G.K., De Guzman, R.N., Turner, R.B., Chancellor, K.J., Wu, Z.R., and Summers, M.F. (2000) NMR structure of the HIV-1 nucleocapsid protein bound to stem-loop SL2 of the psi-RNA packaging signal. Implications for genome recognition. J Mol Biol. 301, 491–511.

    Article  PubMed  CAS  Google Scholar 

  38. De Guzman, R.N., Wu, Z.R., Stalling, C.C., Pappalardo, L., Borer, P.N., and Summers, M.F. (1998) Structure of the HIV-1 nucleocapsid protein bound to the SL3 psi-RNA recognition element. Science. 279, 384–388.

    Article  PubMed  Google Scholar 

  39. Johnson, P.E., Turner, R.B., Wu, Z.R., Hairston, L., Guo, J., Levin, J.G., and Summers, M.F. (2000) A mechanism for plus-strand transfer enhancement by the HIV-1 nucleocapsid protein during reverse transcription. Biochemistry. 39, 9084–9091.

    Article  PubMed  CAS  Google Scholar 

  40. Bourbigot, S., Ramalanjaona, N., Boudier, C., Salgado, G.F., Roques, B.P., Mely, Y., Bouaziz, S., and Morellet, N. (2008) How the HIV-1 nucleocapsid protein binds and destabilises the (–)primer binding site during reverse transcription. J Mol Biol. 383, 1112–1128.

    Article  PubMed  CAS  Google Scholar 

  41. Taylor, G.A., Carballo, E., Lee, D.M., Lai, W.S., Thompson, M.J., Patel, D.D., Schenkman, D.I., Gilkeson, G.S., Broxmeyer, H.E., Haynes, B.F., and Blackshear, P.J. (1996) A pathogenetic role for TNF alpha in the syndrome of cachexia, arthritis, and autoimmunity resulting from tristetraprolin (TTP) deficiency. Immunity. 4, 445–454.

    Article  PubMed  CAS  Google Scholar 

  42. Lai, W.S., Carballo, E., Strum, J.R., Kennington, E.A., Phillips, R.S., and Blackshear, P.J. (1999) Evidence that tristetraprolin binds to AU-rich elements and promotes the deadenylation and destabilization of tumor necrosis factor alpha mRNA. Mol Cell Biol. 19, 4311–4323.

    PubMed  CAS  Google Scholar 

  43. Liang, J., Wang, J., Azfer, A., Song, W., Tromp, G., Kolattukudy, P.E., and Fu, M. (2008) A novel CCCH-zinc finger protein family regulates proinflammatory activation of macrophages. J Biol Chem. 283, 6337–6346.

    Article  PubMed  CAS  Google Scholar 

  44. DuBois, R.N., McLane, M.W., Ryder, K., Lau, L.F., and Nathans, D. (1990) A growth factor-inducible nuclear protein with a novel cysteine/histidine repetitive sequence. J Biol Chem. 265, 19185–19191.

    PubMed  CAS  Google Scholar 

  45. Barabino, S.M., Ohnacker, M., and Keller, W. (2000) Distinct roles of two Yth1p domains in 3′-end cleavage and polyadenylation of yeast pre-mRNAs. EMBO J. 19, 3778–3787.

    Article  PubMed  CAS  Google Scholar 

  46. Vinuesa, C.G., Cook, M.C., Angelucci, C., Athanasopoulos, V., Rui, L., Hill, K.M., Yu, D., Domaschenz, H., Whittle, B., Lambe, T., Roberts, I.S., Copley, R.R., Bell, J.I., Cornall, R.J., and Goodnow, C.C. (2005) A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity. Nature. 435, 452–458.

    Article  PubMed  CAS  Google Scholar 

  47. Yu, D., Tan, A.H., Hu, X., Athanasopoulos, V., Simpson, N., Silva, D.G., Hutloff, A., Giles, K.M., Leedman, P.J., Lam, K.P., Goodnow, C.C., and Vinuesa, C.G. (2007) Roquin represses autoimmunity by limiting inducible T-cell co-stimulator messenger RNA. Nature. 450, 299–303.

    Article  PubMed  CAS  Google Scholar 

  48. Guo, X., Carroll, J.W., Macdonald, M.R., Goff, S.P., and Gao, G. (2004) The zinc finger antiviral protein directly binds to specific viral mRNAs through the CCCH zinc finger motifs. J Virol. 78, 12781–12787.

    Article  PubMed  CAS  Google Scholar 

  49. Stumpo, D.J., Broxmeyer, H.E., Ward, T., Cooper, S., Hangoc, G., Chung, Y.J., Shelley, W.C., Richfield, E.K., Ray, M.K., Yoder, M.C., Aplan, P.D., and Blackshear, P.J. (2009) Targeted disruption of Zfp36l2, encoding a CCCH tandem zinc finger RNA-binding protein, results in defective hematopoiesis. Blood.

    Google Scholar 

  50. Hudson, B.P., Martinez-Yamout, M.A., Dyson, H.J., and Wright, P.E. (2004) Recognition of the mRNA AU-rich element by the zinc finger domain of TIS11d. Nat Struct Mol Biol. 11, 257–264.

    Article  PubMed  CAS  Google Scholar 

  51. Lai, W.S., Kennington, E.A., and Blackshear, P.J. (2002) Interactions of CCCH zinc finger proteins with mRNA: non-binding tristetraprolin mutants exert an inhibitory effect on degradation of AU-rich element-containing mRNAs. J Biol Chem. 277, 9606–9613.

    Article  PubMed  CAS  Google Scholar 

  52. Ranum, L.P. and Cooper, T.A. (2006) RNA-mediated neuromuscular disorders. Annu Rev Neurosci. 29, 259–277.

    Article  PubMed  CAS  Google Scholar 

  53. Vicente, M., Monferrer, L., Poulos, M.G., Houseley, J., Monckton, D.G., O’dell, K.M., Swanson, M.S., and Artero, R.D. (2007) Muscleblind isoforms are functionally distinct and regulate alpha-actinin splicing. Differentiation. 75, 427–440.

    Article  PubMed  CAS  Google Scholar 

  54. Fardaei, M., Rogers, M.T., Thorpe, H.M., Larkin, K., Hamshere, M.G., Harper, P.S., and Brook, J.D. (2002) Three proteins, MBNL, MBLL and MBXL, co-localize in vivo with nuclear foci of expanded-repeat transcripts in DM1 and DM2 cells. Hum Mol Genet. 11, 805–814.

    Article  PubMed  CAS  Google Scholar 

  55. Miller, J.W., Urbinati, C.R., Teng-Umnuay, P., Stenberg, M.G., Byrne, B.J., Thornton, C.A., and Swanson, M.S. (2000) Recruitment of human muscleblind proteins to (CUG)(n) expansions associated with myotonic dystrophy. EMBO J. 19, 4439–4448.

    Article  PubMed  CAS  Google Scholar 

  56. Higa, M.M., Alam, S.L., Sundquist, W.I., and Ullman, K.S. (2007) Molecular characterization of the Ran-binding zinc finger domain of Nup153. J Biol Chem. 282, 17090–17100.

    Article  PubMed  CAS  Google Scholar 

  57. Alam, S.L., Sun, J., Payne, M., Welch, B.D., Blake, B.K., Davis, D.R., Meyer, H.H., Emr, S.D., and Sundquist, W.I. (2004) Ubiquitin interactions of NZF zinc fingers. EMBO J. 23, 1411–1421.

    Article  PubMed  CAS  Google Scholar 

  58. Jamieson, A.C., Wang, H., and Kim, S.H. (1996) A zinc finger directory for high-affinity DNA recognition. Proc Natl Acad Sci USA. 93, 12834–12839.

    Article  PubMed  CAS  Google Scholar 

  59. Crozat, A., Aman, P., Mandahl, N., and Ron, D. (1993) Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma. Nature. 363, 640–644.

    Article  PubMed  CAS  Google Scholar 

  60. Delattre, O., Zucman, J., Plougastel, B., Desmaze, C., Melot, T., Peter, M., Kovar, H., Joubert, I., de Jong, P., Rouleau, G., et al (1992) Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours. Nature. 359, 162–165.

    Article  PubMed  CAS  Google Scholar 

  61. Gure, A.O., Altorki, N.K., Stockert, E., Scanlan, M.J., Old, L.J., and Chen, Y.T. (1998) Human lung cancer antigens recognized by autologous antibodies: definition of a novel cDNA derived from the tumor suppressor gene locus on chromosome 3p21.3. Cancer Res. 58, 1034–1041.

    PubMed  CAS  Google Scholar 

  62. Nagase, T., Seki, N., Tanaka, A., Ishikawa, K., and Nomura, N. (1995) Prediction of the coding sequences of unidentified human genes. IV. The coding sequences of 40 new genes (KIAA0121-KIAA0160) deduced by analysis of cDNA clones from human cell line KG-1. DNA Res. 2(167–74), 99–210.

    Google Scholar 

  63. Morohoshi, F., Arai, K., Takahashi, E.I., Tanigami, A., and Ohki, M. (1996) Cloning and mapping of a human RBP56 gene encoding a putative RNA binding protein similar to FUS/TLS and EWS proteins. Genomics. 38, 51–57.

    Article  PubMed  CAS  Google Scholar 

  64. Wang, P.J., McCarrey, J.R., Yang, F., and Page, D.C. (2001) An abundance of X-linked genes expressed in spermatogonia. Nat Genet. 27, 422–426.

    Article  PubMed  Google Scholar 

  65. Loughlin, F.E., Mansfield, R.E., Vaz, P.M., McGrath, A.P., Setiyaputra, S., Gamsjaeger, R., Chen, E.S., Morris, B.J., Guss, J.M., and Mackay, J.P. (2009) The zinc fingers of the SR-like protein ZRANB2 are single-stranded RNA-binding domains that recognize 5′ splice site-like sequences. Proc Natl Acad Sci USA. 106, 5581–5586.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Springer Science+Business Media, LLC

About this protocol

Cite this protocol

Font, J., Mackay, J.P. (2010). Beyond DNA: Zinc Finger Domains as RNA-Binding Modules. In: Mackay, J., Segal, D. (eds) Engineered Zinc Finger Proteins. Methods in Molecular Biology, vol 649. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60761-753-2_29

Download citation

  • DOI: https://doi.org/10.1007/978-1-60761-753-2_29

  • Published:

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-60761-752-5

  • Online ISBN: 978-1-60761-753-2

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics