The CUG-Binding Protein Binds Specifically to UG Dinucleotide Repeats in a Yeast Three-Hybrid System

Takahashi, Nobuhiro; Sasagawa, Noboru; Suzuki, Koichi; Ishiura, Shoichi

doi:10.1006/bbrc.2000.3694

Cited by 78 publications

(71 citation statements)

References 23 publications

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“…The high sequence binding specificity of TDP-43 is also highlighted by the fact that addition of cold TAR RNA was incapable of competing with the binding of GST-TDP43 to the (UG) 12 sequence, a finding that had already been described in the original isolation of TDP-43 (19) and which we confirm here. It should be noted that at present no other RNA-binding protein has been described to bind UG-repeated sequences although CUG-BP (CUG-binding protein) has been recently described to bind UG repeats in a yeast three-hybrid system (20).…”

Section: Resultsmentioning

confidence: 99%

Characterization and Functional Implications of the RNA Binding Properties of Nuclear Factor TDP-43, a Novel Splicing Regulator ofCFTR Exon 9

Buratti

Baralle

2001

Journal of Biological Chemistry

617

606

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Variations in a polymorphic (TG)m sequence near exon 9 of the human CFTR gene have been associated with variable proportions of exon skipping and occurrence of disease. We have recently identified nuclear factor TDP-43 as a novel splicing regulator capable of binding to this element in the CFTR pre-mRNA and inhibiting recognition of the neighboring exon. In this study we report the dissection of the RNA binding properties of TDP-43 and their functional implications in relationship with the splicing process. Our results show that this protein contains two fully functional RNA recognition motif (RRM) domains with distinct RNA/DNA binding characteristics. Interestingly, TDP-43 can bind a minimum number of six UG (or TG) single-stranded dinucleotide stretches, and binding affinity increases with the number of repeats. In particular, the highly conserved Phe residues in the first RRM region play a key role in nucleic acid recognition.We have recently reported the identification of TDP-43 as a splicing regulator that specifically binds the (UG)m-repeated polymorphic region near the 3Ј-splice site of CFTR exon 9 and down-regulates its recognition by the splicing machinery (1). This region, acting in concert with the adjacent (u)n element, is one of the key cis-acting sequences which regulate the proportion of exon 9 skipping in the mature CFTR mRNA transcript (1-3). Considering that exon 9 skipping produces a non-functional CFTR protein (4, 5) the study of the RNA binding properties of TDP-43 is of considerable importance to gain further insight concerning the potential disease-causing consequences of its binding in vivo. Indeed, the clinical relevance of these studies is highlighted by the existence of a clear association between certain (TG)m(T)n alleles with distinct forms of Cystic Fibrosis (1, 6 -9).In addition, the study of (UG)m elements can provide further insight concerning the mRNA splicing process in general because (UG)m sequences have been described to act as splicing regulatory sequences in different genomic contexts. In fact, in addition to the CFTR gene, the presence of simple (UG)mrepeated sequences has been described to influence the splicing process of at least two other genes: the apolipoprotein AII gene (10) and the human cardiac Na ϩ /Ca 2ϩ exchanger (11). In the Apo AII gene the UG tract was shown to be functionally equivalent to a polypyrimidine tract and required for efficient splicing of Apo AII exon 2 (10) while in the human cardiac Na ϩ /Ca 2ϩ exchanger (11) it acts as a strong intronic splicing enhancer situated in intron 2. It should be noted that in contrast with these two genes, the CFTR (UG)m element was found to possess a strong inhibitory effect on CFTR exon 9 splicing, a property that may probably be linked to its peculiar evolutionary history. In fact, sequencing of the mouse CFTR exon 9 genomic region has shown that in the flanking introns, the (TG)m(T)n regulatory elements are absent and that the intron themselves are of very different length when compared with the human introns (...

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Section: Resultsmentioning

confidence: 99%

Characterization and Functional Implications of the RNA Binding Properties of Nuclear Factor TDP-43, a Novel Splicing Regulator ofCFTR Exon 9

Buratti

Baralle

2001

Journal of Biological Chemistry

617

606

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“…EDEN and EDEN-BP may also mediate maternal transcript deadenylation in other organisms: in Drosophila, artificial messages containing a synthetic EDEN motif are not translated in oocytes (Ezzeddine et al, 2002). Furthermore, EDEN-BP homologs have been identified in Drosophila (Bruno-3), zebrafish, (Bru1), and human (CUG-BP; Suzuki et al, 2000;Takahashi et al, 2000;Delaunay et al, 2004).…”

Section: Maternal Transcript Degradationmentioning

confidence: 99%

Transitioning from egg to embryo: Triggers and mechanisms of egg activation

Horner

Wolfner

2008

Developmental Dynamics

181

177

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The transition from mature oocyte to developing embryo requires a coordinated series of events, collectively known as egg activation. Egg activation includes changes to egg coverings to prevent polyspermy, release of oocyte meiotic arrest, generation of haploid female and male pronuclei, changes in maternal mRNAs and protein populations, and cytoskeletal rearrangements. In many animals, egg activation is triggered by fertilization, which increases intracellular calcium within the oocyte and thereby regulates molecular events of egg activation. In other animals, fertilization-independent external signals, including mechanical stimulation of eggs and/or changes in ionic milieu, trigger activation. Recent studies have clarified the upstream portion of pathways leading to eggshell changes and cell cycle resumption and have identified activation-induced changes in maternal mRNA and protein profiles that can identify molecular players in the downstream events of egg activation. We review signals that trigger activation and how they link to subsequent molecular events of egg activation. Developmental Dynamics 237:527-544, 2008.

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“…This sequence resembled previously characterized binding sites for CELF1 [31], [32], and CELF1 was found to bind with high affinity to GRE sequences and mediate mRNA degradation [30]. This chapter reviews how CELF1 and its target transcripts function as an evolutionarily conserved posttranscriptional regulatory network which plays important roles in health and disease.…”

Section: Introductionmentioning

confidence: 52%