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A Drosophila fragile X protein interacts with components of RNAi and ribosomal proteins

Ishizuka, Akira, Siomi, Mikiko C., Siomi, Haruhiko·2002·Genes & Development
DOI 10.1101/gad.1022002
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Abstract

Fragile X syndrome is a common form of inherited mental retardation caused by the loss of FMR1 expression. The FMR1 gene encodes an RNA-binding protein that associates with translating ribosomes and acts as a negative translational regulator. In Drosophila , the fly homolog of the FMR1 protein (dFMR1) binds to and represses the translation of an mRNA encoding of the microtuble-associated protein Futsch. We have isolated a dFMR1-associated complex that includes two ribosomal proteins, L5 and L11, along with 5S RNA. The dFMR1 complex also contains Argonaute2 (AGO2) and a Drosophila homolog of p68 RNA helicase (Dmp68). AGO2 is an essential component for the RNA-induced silencing complex (RISC), a sequence-specific nuclease complex that mediates RNA interference (RNAi) in Drosophila . We show that Dmp68 is also required for efficient RNAi. We further show that dFMR1 is associated with Dicer, another essential component of the RNAi pathway, and microRNAs (miRNAs) in vivo, suggesting that dFMR1 is part of the RNAi-related apparatus. Our findings suggest a model in which the RNAi and dFMR1-mediated translational control pathways intersect in Drosophila. Our findings also raise the possibility that defects in an RNAi-related machinery may cause human disease.

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  • The lack of a canonical miRNA/siRNA binding domain in FMRP suggests that miRNAs are indirectly associated with FMRP, possibly through Argonaute proteins.

    “The lack of a canonical miRNA/siRNA binding domain in FMRP suggests that miRNAs are indirectly associated with FMRP, possibly through Argonaute proteins which contain a miRNA binding domain and interact with FMRP in an RNA-independent manner (Caudy et al., 2002; Ishizuka et al., 2002).”

    From Regulation of Synaptic Structure and Function by FMRP-Associated MicroRNAs miR-125b and miR-132 (2010) · cites this paper as Ishizuka et al., 2002

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Research works printed but not linked: 7

  1. Clemens, J.C., Worby, C.A., Simonson-Leff, N., Muda, M., Mae- hama, T., Hemmings, B.A., and Dixon, J.E. 2000. Use of double-stranded RNA interference in Drosophila cell lines to dissect signal transduction pathways. Proc. Natl. Acad. Sci. 97: 6499-6503.
  2. Fagard, M., Boutet, S., Morel, J.B., Bellini, C., and Vaucheret, H. 2000. AGO1, QDE-2, and RDE-1 are related proteins re- quired for post-transcriptional gene silencing in plants, quelling in fungi, and RNA interference in animals. Proc. Natl. Acad. Sci. 97: 11650-11654.
  3. Greenough, W.T., Klintsova, A.Y., Irwin, S.A., Galvez, R., Bates, K.E., and Weiler, I.J. 2001. Synaptic regulation of protein synthesis and the fragile X protein. Proc. Natl. Acad. Sci. 98: 7101-7106.
  4. R.J. Hagerman and P.J. Hagerma), pp. 3-109.
  5. Imbert, G., Feng, Y., Nelson, D.L., Warren, S.T., and Mandel, J.-L. 1998. FMR1 and mutations in fragile X syndrome: Mo- lecular biology, biochemistry, and genetics. In Genetic in- stabilities and hereditary neurological diseases. (eds. R.D. Wells and S.T. Warren), pp. 27-53. Academic Press, San Diego, CA.
  6. Moore, P.B. 1996. The structure and function of 5S ribosomal RNA. In Ribosomal RNA and structure, evolution, process- ing and function in protein biosynthesis (eds. R.A. Zimmer- mann and A.E. Dahlberg), pp. 199-236. CRC Press, Boca Ra- ton, FL.
  7. Williams, R.W. and Rubin, G.M. 2002. ARGONAUTE1 is re- quired for efficient RNA interference in Drosophila em- bryos. Proc. Natl. Acad. Sci. 99: 6889-6894.

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Authors
Ishizuka, A., Siomi, M. C., & Siomi, H.
Venue
Genes & Development
Publisher
Cold Spring Harbor Laboratory
Published
2002-10-01
Volume
16
Issue
19
Pages
2497-2508
ISSN
  • 0890-9369
  • 1549-5477
DOI
10.1101/gad.1022002
Cited by
486
References
3
Language
en

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