The fragile X mental retardation protein has nucleic acid chaperone properties.

The fragile X syndrome is the most common cause of inherited mental retardation resulting from the absence of the fragile X mental retardation protein (FMRP). FMRP contains two K-homology (KH) domains and one RGG box that are landmarks characteristic of RNA-binding proteins. In agreement with this, FMRP associates with messenger ribonucleoparticles (mRNPs) within actively translating ribosomes, and is thought to regulate translation of target mRNAs, including its own transcript. To investigate whether FMRP might chaperone nucleic acid folding and hybridization, we analysed the annealing and strand exchange activities of DNA oligonucleotides and the enhancement of ribozyme-directed RNA substrate cleavage by FMRP and deleted variants relative to canonical nucleic acid chaperones, such as the cellular YB-1/p50 protein and the retroviral nucleocapsid protein HIV-1 NCp7. FMRP was found to possess all the properties of a potent nucleic acid chaperone, requiring the KH motifs and RGG box for optimal activity. These findings suggest that FMRP may regulate translation by acting on RNA-RNA interactions and thus on the structural status of mRNAs.

[1]  H. Izumi,et al.  Characterization of the 5'-untranslated region of YB-1 mRNA and autoregulation of translation by YB-1 protein. , 2004, Nucleic acids research.

[2]  É. Khandjian,et al.  Fragile X Mental Retardation protein determinants required for its association with polyribosomal mRNPs. , 2003, Human molecular genetics.

[3]  A. Ramos,et al.  G-quartet-dependent recognition between the FMRP RGG box and RNA. , 2003, RNA.

[4]  L. Chen,et al.  The fragile x mental retardation protein binds and regulates a novel class of mRNAs containing u rich target sequences , 2003, Neuroscience.

[5]  I. Weiler,et al.  NUFIP1 (nuclear FMRP interacting protein 1) is a nucleocytoplasmic shuttling protein associated with active synaptoneurosomes. , 2003, Experimental cell research.

[6]  A. Pastore,et al.  The N-terminus of the fragile X mental retardation protein contains a novel domain involved in dimerization and RNA binding. , 2003, Biochemistry.

[7]  É. Khandjian,et al.  82-FIP, a novel FMRP (fragile X mental retardation protein) interacting protein, shows a cell cycle-dependent intracellular localization. , 2003, Human molecular genetics.

[8]  H. Izumi,et al.  The pleiotropic functions of the Y-box-binding protein, YB-1. , 2003, BioEssays : news and reviews in molecular, cellular and developmental biology.

[9]  P. Jin,et al.  New insights into fragile X syndrome: from molecules to neurobehaviors. , 2003, Trends in biochemical sciences.

[10]  G. Bassell,et al.  Sunrise at the Synapse The FMRP mRNP Shaping the Synaptic Interface , 2003, Neuron.

[11]  B. Oostra,et al.  The Fragile X Syndrome Protein FMRP Associates with BC1 RNA and Regulates the Translation of Specific mRNAs at Synapses , 2003, Cell.

[12]  I. Weiler,et al.  RNA Cargoes Associating with FMRP Reveal Deficits in Cellular Functioning in Fmr1 Null Mice , 2003, Neuron.

[13]  É. Khandjian,et al.  Trapping of messenger RNA by Fragile X Mental Retardation protein into cytoplasmic granules induces translation repression. , 2002, Human molecular genetics.

[14]  J. Darlix,et al.  A 5′–3′ long‐range interaction in Ty1 RNA controls its reverse transcription and retrotransposition , 2002, The EMBO journal.

[15]  J. Mandel,et al.  Advances in understanding of fragile X pathogenesis and FMRP function, and in identification of X linked mental retardation genes. , 2002, Current opinion in genetics & development.

[16]  Stephen T Warren,et al.  A decade of molecular studies of fragile X syndrome. , 2002, Annual review of neuroscience.

[17]  J. Darlix,et al.  The ubiquitous nature of RNA chaperone proteins. , 2002, Progress in nucleic acid research and molecular biology.

[18]  V. Evdokimova,et al.  The Major Messenger Ribonucleoprotein Particle Protein p50 (YB-1) Promotes Nucleic Acid Strand Annealing* , 2001, The Journal of Biological Chemistry.

[19]  J. Darnell,et al.  Microarray Identification of FMRP-Associated Brain mRNAs and Altered mRNA Translational Profiles in Fragile X Syndrome , 2001, Cell.

[20]  J. Darnell,et al.  Fragile X Mental Retardation Protein Targets G Quartet mRNAs Important for Neuronal Function , 2001, Cell.

[21]  C. Ehresmann,et al.  The fragile X mental retardation protein binds specifically to its mRNA via a purine quartet motif , 2001, The EMBO journal.

[22]  J. Mandel,et al.  A highly conserved protein family interacting with the fragile X mental retardation protein (FMRP) and displaying selective interactions with FMRP-related proteins FXR1P and FXR2P , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[23]  S. Warren,et al.  The fragile X mental retardation protein inhibits translation via interacting with mRNA. , 2001, Nucleic acids research.

[24]  A. Ostareck-Lederer,et al.  Evidence that fragile X mental retardation protein is a negative regulator of translation. , 2001, Human molecular genetics.

[25]  F. Bushman,et al.  Nucleic Acid Chaperone Activity of the ORF1 Protein from the Mouse LINE-1 Retrotransposon , 2001, Molecular and Cellular Biology.

[26]  W. Brown,et al.  RNAs that interact with the fragile X syndrome RNA binding protein FMRP. , 2000, Biochemical and biophysical research communications.

[27]  M Rau,et al.  Nucleocapsid protein of human immunodeficiency virus as a model protein with chaperoning functions and as a target for antiviral drugs. , 2000, Advances in pharmacology.

[28]  D. Ficheux,et al.  The yeast Ty3 retrotransposon contains a 5′–3′ bipartite primer‐binding site and encodes nucleocapsid protein NCp9 functionally homologous to HIV‐1 NCp7 , 1998, The EMBO journal.

[29]  A. Rein,et al.  Nucleic-acid-chaperone activity of retroviral nucleocapsid proteins: significance for viral replication. , 1998, Trends in biochemical sciences.

[30]  D. Absher,et al.  FMRP associates with polyribosomes as an mRNP, and the I304N mutation of severe fragile X syndrome abolishes this association. , 1997, Molecular cell.

[31]  É. Khandjian,et al.  The fragile X mental retardation protein is associated with poly(A)+ mRNA in actively translating polyribosomes. , 1997, Human molecular genetics.

[32]  I. Weiler,et al.  Fragile X mental retardation protein is translated near synapses in response to neurotransmitter activation. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[33]  S. Hersch,et al.  Fragile X Mental Retardation Protein: Nucleocytoplasmic Shuttling and Association with Somatodendritic Ribosomes , 1997, The Journal of Neuroscience.

[34]  É. Khandjian,et al.  The fragile X mental retardation protein is associated with ribosomes , 1996, Nature Genetics.

[35]  D. Herschlag.  RNA Chaperones and the RNA Folding Problem (*) , 1995, The Journal of Biological Chemistry.

[36]  J. Mandel,et al.  A heterogeneous set of FMR1 proteins is widely distributed in mouse tissues and is modulated in cell culture. , 1995, Human molecular genetics.

[37]  J. Rossi,et al.  Facilitation of hammerhead ribozyme catalysis by the nucleocapsid protein of HIV‐1 and the heterogeneous nuclear ribonucleoprotein A1. , 1994, The EMBO journal.

[38]  D. Herschlag,et al.  Protein enhancement of hammerhead ribozyme catalysis. , 1993, Science.

[39]  J. Mandel,et al.  The FMR–1 protein is cytoplasmic, most abundant in neurons and appears normal in carriers of a fragile X premutation , 1993, Nature Genetics.

[40]  B. Roques,et al.  Viral RNA annealing activities of human immunodeficiency virus type 1 nucleocapsid protein require only peptide domains outside the zinc fingers. , 1992, Proceedings of the National Academy of Sciences of the United States of America.