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Exon

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Serge Hardy - One of the best experts on this subject based on the ideXlab platform.

  • Polypyrimidine tract binding protein prevents activity of an intronic regulatory element that promotes usage of a composite 3'-terminal Exon.
    Journal of Biological Chemistry, 2009
    Co-Authors: Vincent Anquetil, Sandra Hamon, Caroline Le Sommer, Agnès Méreau, Hubert Lerivray, Serge Hardy
    Abstract:

    Alternative splicing of 3'-terminal Exons plays a critical role in gene expression by producing mRNA with distinct 3'-untranslated regions that regulate their fate and their expression. The Xenopus alpha-tropomyosin pre-mRNA possesses a composite internal/3'-terminal Exon (Exon 9A9') that is differentially processed depending on the embryonic tissue. Exon 9A9' is repressed in non-muscle tissue by the polypyrimidine tract binding protein, whereas it is selected as a 3'-terminal or internal Exon in myotomal cells and adult striated muscles, respectively. We report here the identification of an intronic regulatory element, designated the upstream terminal Exon enhancer (UTE), that is required for the specific usage of Exon 9A9' as a 3'-terminal Exon in the myotome. We demonstrate that polypyrimidine tract binding protein prevents the activity of UTE in non-muscle cells, whereas a subclass of serine/arginine rich (SR) proteins promotes the selection of Exon 9A9' in a UTE-dependent way. Morpholino-targeted blocking of UTE in the embryo strongly reduced the inclusion of Exon 9A9' as a 3'-terminal Exon in the endogenous mRNA, demonstrating the function of UTE under physiological circumstances. This strategy allowed us to reveal a splicing pathway that generates a mRNA with no in frame stop codon and whose steady-state level is translation-dependent. This result suggests that a non-stop decay mechanism participates in the strict control of the 3'-end processing of the alpha-tropomyosin pre-mRNA.

  • Polypyrimidine Tract-binding Protein Is Involved in Vivo in Repression of a Composite Internal/3′ -Terminal Exon of the Xenopus α-Tropomyosin Pre-mRNA
    Journal of Biological Chemistry, 2004
    Co-Authors: Sandra Hamon, Caroline Le Sommer, Agnès Méreau, Marie-rose Allo, Serge Hardy
    Abstract:

    The Xenopus alpha(fast)-tropomyosin gene contains, at its 3' -end, a composite internal/3' -terminal Exon (Exon 9A9'), which is subjected to three different patterns of splicing according to the cell type. Exon 9A9' is included as a terminal Exon in the myotome and as an internal Exon in adult striated muscles, whereas it is skipped in nonmuscle cells. We have developed an in vivo model based on transient expression of minigenes encompassing the regulated Exon 9A9' in Xenopus oocytes and embryos. We first show that the different alpha-tropomyosin minigenes recapitulate the splicing pattern of the endogenous gene and constitute valuable tools to seek regulatory sequences involved in Exon 9A9' usage. A mutational analysis led to the identification of an intronic element that is involved in the repression of Exon 9A9' in nonmuscle cells. This element harbors four polypyrimidine track-binding protein (PTB) binding sites that are essential for the repression of Exon 9A9'. We show using UV cross-linking and immunoprecipitation experiments that Xenopus PTB (XPTB) interacts with these PTB binding sites. Finally, we show that depletion of endogenous XPTB in Xenopus embryos using a morpholinobased translational inhibition strategy resulted in Exon 9A9' inclusion in embryonic epidermal cells. These results demonstrate that XPTB is required in vivo to repress the terminal Exon 9A9' and suggest that PTB could be a major actor in the repression of regulated 3' -terminal Exon.

Heegyum Moon - One of the best experts on this subject based on the ideXlab platform.

  • hnrnp m facilitates Exon 7 inclusion of smn2 pre mrna in spinal muscular atrophy by targeting an enhancer on Exon 7
    Biochimica et Biophysica Acta, 2014
    Co-Authors: Heegyum Moon, Xuexiu Zheng, Huyn Kyung Oh, Jangsoo Chun, Woo Keun Song, Hyon E Choy, Haihong Shen
    Abstract:

    Spinal muscular atrophy (SMA) is an autosomal recessive genetic disease, which causes death of motor neurons in the anterior horn of the spinal cord. Genetic cause of SMA is the deletion or mutation of SMN1 gene, which encodes the SMN protein. Although SMA patients include SMN2 gene, a duplicate of SMN1 gene, predominant production of Exon 7 skipped isoform from SMN2 pre-mRNA, fails to rescue SMA patients. Here we show that hnRNP M, a member of hnRNP protein family, when knocked down, promotes Exon 7 skipping of both SMN2 and SMN1 pre-mRNA. By contrast, overexpression of hnRNP M promotes Exon 7 inclusion of both SMN2 and SMN1 pre-mRNA. Significantly, hnRNP M promotes Exon 7 inclusion in SMA patient cells. Thus, we conclude that hnRNP M promotes Exon 7 inclusion of both SMN1 and SMN2 pre-mRNA. We also demonstrate that hnRNP M contacts an enhancer on Exon 7, which was previously shown to provide binding site for tra2β. We present evidence that hnRNP M and tra2β contact overlapped sequence on Exon 7 but with slightly different RNA sequence requirements. In addition, hnRNP M promotes U2AF65 recruitment on the flanking intron of Exon 7. We conclude that hnRNP M promotes Exon 7 inclusion of SMN1 and SMN2 pre-mRNA through targeting an enhancer on Exon 7 through recruiting U2AF65. Our results provide a clue that hnRNP M is a potential therapeutic target for SMA.

  • HnRNP A1 contacts Exon 5 to promote Exon 6 inclusion of apoptotic Fas gene
    Apoptosis, 2013
    Co-Authors: Hyun-kyung Oh, Youngsoo Jun, Tiing Jen Loh, Sunghee Cho, Eunkyung Lee, Ha-na Jang, Heegyum Moon, Zhi Sheng, Jaehoon Lee, Jianhua Zhou
    Abstract:

    Fas is a transmembrane cell surface protein recognized by Fas ligand (FasL). When FasL binds to Fas, the target cells undergo apoptosis. A soluble Fas molecule that lacks the transmembrane domain is produced from skipping of Exon 6 encoding this region in alternative splicing procedure. The soluble Fas molecule has the opposite function of intact Fas molecule, protecting cells from apoptosis. Here we show that knockdown of hnRNP A1 promotes Exon 6 skipping of Fas pre-mRNA, whereas overexpression of hnRNP A1 reduces Exon 6 skipping. Based on the bioinformatics approach, we have hypothesized that hnRNP A1 functions through interrupting 5' splice site selection of Exon 5 by interacting with its potential binding site close to 5' splice site of Exon 5. Consistent with our hypothesis, we demonstrate that mutations of the hnRNP A1 binding site on Exon 5 disrupted the effects of hnRNP A1 on Exon 6 inclusion. RNA pull-down assay and then western blot analysis with hnRNP A1 antibody prove that hnRNP A1 contacts the potential binding site RNA sequence on Exon 5 but not the mutant sequence. In addition, we show that the mutation of 5' splice site on Exon 5 to a less conserved sequence destructed the effects of hnRNP A1 on Exon 6 inclusion. Therefore we conclude that hnRNP A1 interacts with Exon 5 to promote distal Exon 6 inclusion of Fas pre-mRNA. Our study reveals a novel alternative splicing mechanism of Fas pre-mRNA.

Ravindra N Singh - One of the best experts on this subject based on the ideXlab platform.

  • alternative splicing in spinal muscular atrophy underscores the role of an intron definition model
    RNA Biology, 2011
    Co-Authors: Natalia N Singh, Ravindra N Singh
    Abstract:

    Humans have two nearly identical copies of the Survival Motor Neuron (SMN) gene: SMN1 and SMN2. The two SMN genes code for identical proteins; however, SMN2 predominantly generates a shorter transcript due to skipping of Exon 7, the last coding Exon. Skipping of SMN2 Exon 7 leads to production of a truncated SMN protein that is highly unstable. The inability of SMN2 to compensate for the loss of SMN1 results in spinal muscular atrophy (SMA), the second most prevalent genetic cause of infant mortality. Since SMN2 is almost universally present in SMA patients, correction of SMN2 Exon 7 splicing holds the promise for cure. Consistently, SMN2 Exon 7 splicing has emerged as one of the best studied splicing systems in humans. The vast amount of recent literature provides a clue that SMN2 Exon 7 splicing is regulated by an intron definition mechanism, which does not require cross-Exon communication as prerequisite for Exon inclusion. Our conclusion is based on the prominent role of intronic cis-elements, some of...

Haihong Shen - One of the best experts on this subject based on the ideXlab platform.

  • hnrnp m facilitates Exon 7 inclusion of smn2 pre mrna in spinal muscular atrophy by targeting an enhancer on Exon 7
    Biochimica et Biophysica Acta, 2014
    Co-Authors: Heegyum Moon, Xuexiu Zheng, Huyn Kyung Oh, Jangsoo Chun, Woo Keun Song, Hyon E Choy, Haihong Shen
    Abstract:

    Spinal muscular atrophy (SMA) is an autosomal recessive genetic disease, which causes death of motor neurons in the anterior horn of the spinal cord. Genetic cause of SMA is the deletion or mutation of SMN1 gene, which encodes the SMN protein. Although SMA patients include SMN2 gene, a duplicate of SMN1 gene, predominant production of Exon 7 skipped isoform from SMN2 pre-mRNA, fails to rescue SMA patients. Here we show that hnRNP M, a member of hnRNP protein family, when knocked down, promotes Exon 7 skipping of both SMN2 and SMN1 pre-mRNA. By contrast, overexpression of hnRNP M promotes Exon 7 inclusion of both SMN2 and SMN1 pre-mRNA. Significantly, hnRNP M promotes Exon 7 inclusion in SMA patient cells. Thus, we conclude that hnRNP M promotes Exon 7 inclusion of both SMN1 and SMN2 pre-mRNA. We also demonstrate that hnRNP M contacts an enhancer on Exon 7, which was previously shown to provide binding site for tra2β. We present evidence that hnRNP M and tra2β contact overlapped sequence on Exon 7 but with slightly different RNA sequence requirements. In addition, hnRNP M promotes U2AF65 recruitment on the flanking intron of Exon 7. We conclude that hnRNP M promotes Exon 7 inclusion of SMN1 and SMN2 pre-mRNA through targeting an enhancer on Exon 7 through recruiting U2AF65. Our results provide a clue that hnRNP M is a potential therapeutic target for SMA.

Natalia N Singh - One of the best experts on this subject based on the ideXlab platform.

  • alternative splicing in spinal muscular atrophy underscores the role of an intron definition model
    RNA Biology, 2011
    Co-Authors: Natalia N Singh, Ravindra N Singh
    Abstract:

    Humans have two nearly identical copies of the Survival Motor Neuron (SMN) gene: SMN1 and SMN2. The two SMN genes code for identical proteins; however, SMN2 predominantly generates a shorter transcript due to skipping of Exon 7, the last coding Exon. Skipping of SMN2 Exon 7 leads to production of a truncated SMN protein that is highly unstable. The inability of SMN2 to compensate for the loss of SMN1 results in spinal muscular atrophy (SMA), the second most prevalent genetic cause of infant mortality. Since SMN2 is almost universally present in SMA patients, correction of SMN2 Exon 7 splicing holds the promise for cure. Consistently, SMN2 Exon 7 splicing has emerged as one of the best studied splicing systems in humans. The vast amount of recent literature provides a clue that SMN2 Exon 7 splicing is regulated by an intron definition mechanism, which does not require cross-Exon communication as prerequisite for Exon inclusion. Our conclusion is based on the prominent role of intronic cis-elements, some of...