Abstract
The post-transcriptional regulation of gene expression underlies several critical developmental phenomena. In metazoa, gene products that are expressed, silenced and packaged during oogenesis govern early developmental processes prior to nascent transcription activation. Furthermore, tissue-specific alternative splicing of several transcription factors controls pattern formation and organ development. A highly conserved family of proteins containing a STAR/GSG RNA-binding domain is essential to both processes. Here, we identify the consensus STAR-binding element (SBE) required for specific mRNA recognition by GLD-1, a key regulator of Caenorhabditis elegans germline development. We have identified and verified new GLD-1 repression targets containing this sequence. The results suggest additional functions of GLD-1 in X-chromosome silencing and early embryogenesis. The SBE is present in Quaking and How mRNA targets, suggesting that STAR protein specificity is highly conserved. Similarities between the SBE and the branch-site signal indicate a possible competition mechanism for STAR/GSG regulation of splicing variants.
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References
Curtis, D., Lehmann, R. & Zamore, P.D. Translational regulation in development. Cell 81, 171–178 (1995).
Johnstone, O. & Lasko, P. Translational regulation and RNA localization in Drosophila oocytes and embryos. Annu. Rev. Genet. 35, 365–406 (2001).
Wickens, M., Goodwin, E.B., Kimble, J., Strickland, S. & Hentze, M. Translational control in developmental decisions. in Translational Control of Gene Expression (eds. Sonenberg, N., Hershey, J.W.B. & Matthews, M.B.) 295–370 (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, USA, 2000).
Jan, E., Motzny, C.K., Graves, L.E. & Goodwin, E.B. The STAR protein, GLD-1, is a translational regulator of sexual identity in Caenorhabditis elegans. EMBO J. 18, 258–269 (1999).
Saccomanno, L. et al. The STAR protein QKI-6 is a translational repressor. Proc. Natl. Acad. Sci. USA 96, 12605–12610 (1999).
Nabel-Rosen, H., Dorevitch, N., Reuveny, A. & Volk, T. The balance between two isoforms of the Drosophila RNA-binding protein How controls tendon cell differentiation. Mol. Cell 4, 573–584 (1999).
Matter, N., Herrlich, P. & Konig, H. Signal-dependent regulation of splicing via phosphorylation of Sam68. Nature 420, 691–695 (2002).
Di Fruscio, M. et al. Kep1 interacts genetically with dredd/caspase-8, and kep1 mutants alter the balance of dredd isoforms. Proc. Natl. Acad. Sci. USA 100, 1814–1819 (2003).
Berglund, J.A., Chua, K., Abovich, N., Reed, R. & Rosbash, M. The splicing factor BBP interacts specifically with the pre-mRNA branchpoint sequence UACUAAC. Cell 89, 781–787 (1997).
Vernet, C. & Artzt, K. STAR, a gene family involved in signal transduction and activation of RNA. Trends Genet. 13, 479–484 (1997).
Chen, T., Damaj, B.B., Herrera, C., Lasko, P. & Richard, S. Self-association of the single-KH-domain family members Sam68, GRP33, GLD-1, and Qk1: role of the KH domain. Mol. Cell Biol. 17, 5707–5718 (1997).
Chen, T. & Richard, S. Structure-function analysis of Qk1: a lethal point mutation in mouse quaking prevents homodimerization. Mol. Cell Biol. 18, 4863–4871 (1998).
Berglund, J.A., Fleming, M.L. & Rosbash, M. The KH domain of the branchpoint sequence binding protein determines specificity for the pre-mRNA branchpoint sequence. RNA 4, 998–1006 (1998).
Liu, Z. et al. Structural basis for recognition of the intron branch site RNA by splicing factor 1. Science 294, 1098–1102 (2001).
Jones, A.R., Francis, R. & Schedl, T. GLD-1, a cytoplasmic protein essential for oocyte differentiation, shows stage- and sex-specific expression during Caenorhabditis elegans germline development. Dev. Biol. 180, 165–183 (1996).
Francis, R., Maine, E. & Schedl, T. Analysis of the multiple roles of gld-1 in germline development: interactions with the sex determination cascade and the glp-1 signaling pathway. Genetics 139, 607–630 (1995).
Francis, R., Barton, M.K., Kimble, J. & Schedl, T. gld-1, a tumor suppressor gene required for oocyte development in Caenorhabditis elegans. Genetics 139, 579–606 (1995).
Kuwabara, P.E. & Perry, M.D. It ain't over till it's ova: germline sex determination in C. elegans. Bioessays 23, 596–604 (2001).
Clifford, R. et al. FOG-2, a novel F-box containing protein, associates with the GLD-1 RNA-binding protein and directs male sex determination in the C. elegans hermaphrodite germline. Development 127, 5265–5276 (2000).
Crittenden, S.L. et al. A conserved RNA-binding protein controls germline stem cells in Caenorhabditis elegans. Nature 417, 660–663 (2002).
Zhang, B. et al. A conserved RNA-binding protein that regulates sexual fates in the C. elegans hermaphrodite germ line. Nature 390, 477–484 (1997).
Jan, E., Yoon, J.W., Walterhouse, D., Iannaccone, P. & Goodwin, E.B. Conservation of the C. elegans tra-2 3′UTR translational control. EMBO J. 16, 6301–6313 (1997).
Ramos, A. et al. Role of dimerization in KH/RNA complexes: the example of Nova KH3. Biochemistry 41, 4193–4201 (2002).
Berglund, J.A., Abovich, N. & Rosbash, M. A cooperative interaction between U2AF65 and mBBP/SF1 facilitates branchpoint region recognition. Genes Dev. 12, 858–867 (1998).
Peled-Zehavi, H., Berglund, J.A., Rosbash, M. & Frankel, A.D. Recognition of RNA branch point sequences by the KH domain of splicing factor 1 (mammalian branch point binding protein) in a splicing factor complex. Mol. Cell Biol. 21, 5232–5241 (2001).
Recht, M.I. & Williamson, J.R. Central domain assembly: thermodynamics and kinetics of S6 and S18 binding to an S15-RNA complex. J. Mol. Biol. 313, 35–48 (2001).
Xu, L., Paulsen, J., Yoo, Y., Goodwin, E.B. & Strome, S. Caenorhabditis elegans MES-3 is a target of GLD-1 and functions epigenetically in germline development. Genetics 159, 1007–1017 (2001).
Fong, Y., Bender, L., Wang, W. & Strome, S. Regulation of the different chromatin states of autosomes and X chromosomes in the germline of C. elegans. Science 296, 2235–2238 (2002).
Lee, M.H. & Schedl, T. Identification of in vivo mRNA targets of GLD-1, a maxi-KH motif containing protein required for C. elegans germ cell development. Genes Dev. 15, 2408–2420 (2001).
Grant, B. & Hirsh, D. Receptor-mediated endocytosis in the Caenorhabditis elegans oocyte. Mol. Biol. Cell 10, 4311–26 (1999).
Thatcher, J.D., Fernandez, A.P., Beaster-Jones, L., Haun, C. & Okkema, P.G. The Caenorhabditis elegans peb-1 gene encodes a novel DNA-binding protein involved in morphogenesis of the pharynx, vulva, and hindgut. Dev. Biol. 229, 480–493 (2001).
Ashcroft, N. & Golden, A. CDC-25.1 regulates germline proliferation in Caenorhabditis elegans. Genesis 33, 1–7 (2002).
Capowski, E.E., Martin, P., Garvin, C. & Strome, S. Identification of grandchildless loci whose products are required for normal germline development in the nematode Caenorhabditis elegans. Genetics 129, 1061–1072 (1991).
Mello, C.C. et al. The PIE-1 protein and germline specification in C. elegans embryos. Nature 382, 710–712 (1996).
Seydoux, G. et al. Repression of gene expression in the embryonic germ lineage of C. elegans. Nature 382, 713–716 (1996).
Reese, K.J., Dunn, M.A., Waddle, J.A. & Seydoux, G. Asymmetric segregation of PIE-1 in C. elegans is mediated by two complementary mechanisms that act through separate PIE-1 protein domains. Mol. Cell 6, 445–55 (2000).
Marin, V.A. & Evans, T.C. Translational repression of a C. elegans Notch mRNA by the STAR/KH domain protein GLD-1. Development 130, 2623–2632 (2003).
Li, Z., Zhang, Y., Li, D. & Feng, Y. Destabilization and mislocalization of myelin basic protein mRNAs in quaking dysmyelination lacking the QKI RNA-binding proteins. J. Neurosci. 20, 4944–4953 (2000).
Ainger, K. et al. Transport and localization elements in myelin basic protein mRNA. J. Cell Biol. 138, 1077–87 (1997).
Wu, J.I., Reed, R.B., Grabowski, P.J. & Artzt, K. Function of quaking in myelination: regulation of alternative splicing. Proc. Natl. Acad. Sci. USA 99, 4233–4238 (2002).
Nabel-Rosen, H., Volohonsky, G., Reuveny, A., Zaidel-Bar, R. & Volk, T. Two isoforms of the Drosophila RNA-binding protein, How, act in opposing directions to regulate tendon cell differentiation. Dev. Cell 2, 183–193 (2002).
Zaffran, S., Astier, M., Gratecos, D. & Semeriva, M. The held out wings (how) Drosophila gene encodes a putative RNA-binding protein involved in the control of muscular and cardiac activity. Development 124, 2087–2098 (1997).
Reddy, T.R. et al. Inhibition of HIV replication by dominant negative mutants of Sam68, a functional homolog of HIV-1 Rev. Nat. Med. 5, 635–642 (1999).
Lin, Q., Taylor, S.J. & Shalloway, D. Specificity and determinants of Sam68 RNA binding. Implications for the biological function of K homology domains. J. Biol. Chem. 272, 27274–27280 (1997).
Batey, R.T. & Williamson, J.R. Interaction of the Bacillus stearothermophilus ribosomal protein S15 with 16 S rRNA: I. Defining the minimal RNA site. J. Mol. Biol. 261, 536–549 (1996).
Acknowledgements
We thank K. Lehmann, M. Recht and M. Trevathan for helpful discussions and critical comments concerning this manuscript, A. Manuell and Y. Pavlova for assistance with construct preparation and S. Bergqvist for assistance with ITC experiments. We also thank the C. elegans Genetic Center for worm strains. S.P.R. was supported by a Damon Runyon Fellowship Award. This work was funded by The Skaggs Institute for Chemical Biology and by US National Institutes of Health grants to J.R.W. and E.B.G.
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Ryder, S., Frater, L., Abramovitz, D. et al. RNA target specificity of the STAR/GSG domain post-transcriptional regulatory protein GLD-1. Nat Struct Mol Biol 11, 20–28 (2004). https://doi.org/10.1038/nsmb706
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DOI: https://doi.org/10.1038/nsmb706
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