The Experts below are selected from a list of 96 Experts worldwide ranked by ideXlab platform

Torben Heick Jensen - One of the best experts on this subject based on the ideXlab platform.

  • SMG6 promotes endonucleolytic cleavage of nonsense mRNA in human cells
    Nature Structural & Molecular Biology, 2009
    Co-Authors: Andrea B. Eberle, Søren Lykke-andersen, Oliver Mühlemann, Torben Heick Jensen
    Abstract:

    Nonsense-mediated decay (NMD) is an mRNA surveillance process that targets transcripts containing a premature stop codon for degradation. Evidence now suggests that mammalian NMD involves an endonucleolytic cleavage that is mediated by human SMG6. From yeast to humans, mRNAs harboring premature termination codons (PTCs) are recognized and degraded by nonsense-mediated mRNA decay (NMD). However, degradation mechanisms of NMD have been suggested to differ between species. In Drosophila melanogaster , NMD is initiated by endonucleolysis near the PTC, whereas in yeast and human cells the current view posits that NMD occurs by exonucleolysis from one or both RNA termini. Here we report that degradation of human nonsense mRNAs can be initiated by PTC-proximal endonucleolytic cleavage. We identify the metazoan-specific NMD factor SMG6 as the responsible endonuclease by demonstrating that mutation of conserved residues in its nuclease domain—the C-Terminal Pin motif—abolishes endonucleolysis in vivo and in vitro . Our data lead to a revised mechanistic model for degradation of nonsense mRNA in human cells and suggest that endonucleolytic cleavage is a conserved feature in metazoan NMD.

  • SMG6 promotes endonucleolytic cleavage of nonsense mRNA in human cells
    Nature structural & molecular biology, 2008
    Co-Authors: Andrea B. Eberle, Søren Lykke-andersen, Oliver Mühlemann, Torben Heick Jensen
    Abstract:

    From yeast to humans, mRNAs harboring premature termination codons (PTCs) are recognized and degraded by nonsense-mediated mRNA decay (NMD). However, degradation mechanisms of NMD have been suggested to differ between species. In Drosophila melanogaster, NMD is initiated by endonucleolysis near the PTC, whereas in yeast and human cells the current view posits that NMD occurs by exonucleolysis from one or both RNA termini. Here we report that degradation of human nonsense mRNAs can be initiated by PTC-proximal endonucleolytic cleavage. We identify the metazoan-specific NMD factor SMG6 as the responsible endonuclease by demonstrating that mutation of conserved residues in its nuclease domain--the C-Terminal Pin motif--abolishes endonucleolysis in vivo and in vitro. Our data lead to a revised mechanistic model for degradation of nonsense mRNA in human cells and suggest that endonucleolytic cleavage is a conserved feature in metazoan NMD.

Andrea B. Eberle - One of the best experts on this subject based on the ideXlab platform.

  • SMG6 promotes endonucleolytic cleavage of nonsense mRNA in human cells
    Nature Structural & Molecular Biology, 2009
    Co-Authors: Andrea B. Eberle, Søren Lykke-andersen, Oliver Mühlemann, Torben Heick Jensen
    Abstract:

    Nonsense-mediated decay (NMD) is an mRNA surveillance process that targets transcripts containing a premature stop codon for degradation. Evidence now suggests that mammalian NMD involves an endonucleolytic cleavage that is mediated by human SMG6. From yeast to humans, mRNAs harboring premature termination codons (PTCs) are recognized and degraded by nonsense-mediated mRNA decay (NMD). However, degradation mechanisms of NMD have been suggested to differ between species. In Drosophila melanogaster , NMD is initiated by endonucleolysis near the PTC, whereas in yeast and human cells the current view posits that NMD occurs by exonucleolysis from one or both RNA termini. Here we report that degradation of human nonsense mRNAs can be initiated by PTC-proximal endonucleolytic cleavage. We identify the metazoan-specific NMD factor SMG6 as the responsible endonuclease by demonstrating that mutation of conserved residues in its nuclease domain—the C-Terminal Pin motif—abolishes endonucleolysis in vivo and in vitro . Our data lead to a revised mechanistic model for degradation of nonsense mRNA in human cells and suggest that endonucleolytic cleavage is a conserved feature in metazoan NMD.

  • SMG6 promotes endonucleolytic cleavage of nonsense mRNA in human cells
    Nature structural & molecular biology, 2008
    Co-Authors: Andrea B. Eberle, Søren Lykke-andersen, Oliver Mühlemann, Torben Heick Jensen
    Abstract:

    From yeast to humans, mRNAs harboring premature termination codons (PTCs) are recognized and degraded by nonsense-mediated mRNA decay (NMD). However, degradation mechanisms of NMD have been suggested to differ between species. In Drosophila melanogaster, NMD is initiated by endonucleolysis near the PTC, whereas in yeast and human cells the current view posits that NMD occurs by exonucleolysis from one or both RNA termini. Here we report that degradation of human nonsense mRNAs can be initiated by PTC-proximal endonucleolytic cleavage. We identify the metazoan-specific NMD factor SMG6 as the responsible endonuclease by demonstrating that mutation of conserved residues in its nuclease domain--the C-Terminal Pin motif--abolishes endonucleolysis in vivo and in vitro. Our data lead to a revised mechanistic model for degradation of nonsense mRNA in human cells and suggest that endonucleolytic cleavage is a conserved feature in metazoan NMD.

Søren Lykke-andersen - One of the best experts on this subject based on the ideXlab platform.

  • SMG6 promotes endonucleolytic cleavage of nonsense mRNA in human cells
    Nature Structural & Molecular Biology, 2009
    Co-Authors: Andrea B. Eberle, Søren Lykke-andersen, Oliver Mühlemann, Torben Heick Jensen
    Abstract:

    Nonsense-mediated decay (NMD) is an mRNA surveillance process that targets transcripts containing a premature stop codon for degradation. Evidence now suggests that mammalian NMD involves an endonucleolytic cleavage that is mediated by human SMG6. From yeast to humans, mRNAs harboring premature termination codons (PTCs) are recognized and degraded by nonsense-mediated mRNA decay (NMD). However, degradation mechanisms of NMD have been suggested to differ between species. In Drosophila melanogaster , NMD is initiated by endonucleolysis near the PTC, whereas in yeast and human cells the current view posits that NMD occurs by exonucleolysis from one or both RNA termini. Here we report that degradation of human nonsense mRNAs can be initiated by PTC-proximal endonucleolytic cleavage. We identify the metazoan-specific NMD factor SMG6 as the responsible endonuclease by demonstrating that mutation of conserved residues in its nuclease domain—the C-Terminal Pin motif—abolishes endonucleolysis in vivo and in vitro . Our data lead to a revised mechanistic model for degradation of nonsense mRNA in human cells and suggest that endonucleolytic cleavage is a conserved feature in metazoan NMD.

  • SMG6 promotes endonucleolytic cleavage of nonsense mRNA in human cells
    Nature structural & molecular biology, 2008
    Co-Authors: Andrea B. Eberle, Søren Lykke-andersen, Oliver Mühlemann, Torben Heick Jensen
    Abstract:

    From yeast to humans, mRNAs harboring premature termination codons (PTCs) are recognized and degraded by nonsense-mediated mRNA decay (NMD). However, degradation mechanisms of NMD have been suggested to differ between species. In Drosophila melanogaster, NMD is initiated by endonucleolysis near the PTC, whereas in yeast and human cells the current view posits that NMD occurs by exonucleolysis from one or both RNA termini. Here we report that degradation of human nonsense mRNAs can be initiated by PTC-proximal endonucleolytic cleavage. We identify the metazoan-specific NMD factor SMG6 as the responsible endonuclease by demonstrating that mutation of conserved residues in its nuclease domain--the C-Terminal Pin motif--abolishes endonucleolysis in vivo and in vitro. Our data lead to a revised mechanistic model for degradation of nonsense mRNA in human cells and suggest that endonucleolytic cleavage is a conserved feature in metazoan NMD.

Oliver Mühlemann - One of the best experts on this subject based on the ideXlab platform.

  • SMG6 promotes endonucleolytic cleavage of nonsense mRNA in human cells
    Nature Structural & Molecular Biology, 2009
    Co-Authors: Andrea B. Eberle, Søren Lykke-andersen, Oliver Mühlemann, Torben Heick Jensen
    Abstract:

    Nonsense-mediated decay (NMD) is an mRNA surveillance process that targets transcripts containing a premature stop codon for degradation. Evidence now suggests that mammalian NMD involves an endonucleolytic cleavage that is mediated by human SMG6. From yeast to humans, mRNAs harboring premature termination codons (PTCs) are recognized and degraded by nonsense-mediated mRNA decay (NMD). However, degradation mechanisms of NMD have been suggested to differ between species. In Drosophila melanogaster , NMD is initiated by endonucleolysis near the PTC, whereas in yeast and human cells the current view posits that NMD occurs by exonucleolysis from one or both RNA termini. Here we report that degradation of human nonsense mRNAs can be initiated by PTC-proximal endonucleolytic cleavage. We identify the metazoan-specific NMD factor SMG6 as the responsible endonuclease by demonstrating that mutation of conserved residues in its nuclease domain—the C-Terminal Pin motif—abolishes endonucleolysis in vivo and in vitro . Our data lead to a revised mechanistic model for degradation of nonsense mRNA in human cells and suggest that endonucleolytic cleavage is a conserved feature in metazoan NMD.

  • SMG6 promotes endonucleolytic cleavage of nonsense mRNA in human cells
    Nature structural & molecular biology, 2008
    Co-Authors: Andrea B. Eberle, Søren Lykke-andersen, Oliver Mühlemann, Torben Heick Jensen
    Abstract:

    From yeast to humans, mRNAs harboring premature termination codons (PTCs) are recognized and degraded by nonsense-mediated mRNA decay (NMD). However, degradation mechanisms of NMD have been suggested to differ between species. In Drosophila melanogaster, NMD is initiated by endonucleolysis near the PTC, whereas in yeast and human cells the current view posits that NMD occurs by exonucleolysis from one or both RNA termini. Here we report that degradation of human nonsense mRNAs can be initiated by PTC-proximal endonucleolytic cleavage. We identify the metazoan-specific NMD factor SMG6 as the responsible endonuclease by demonstrating that mutation of conserved residues in its nuclease domain--the C-Terminal Pin motif--abolishes endonucleolysis in vivo and in vitro. Our data lead to a revised mechanistic model for degradation of nonsense mRNA in human cells and suggest that endonucleolytic cleavage is a conserved feature in metazoan NMD.

Sarah F. Newbury - One of the best experts on this subject based on the ideXlab platform.

  • DIS3 isoforms vary in their endoribonuclease activity and are differentially expressed within haematological cancers.
    The Biochemical journal, 2018
    Co-Authors: Sophie R. Robinson, Sandra C. Viegas, Rute G. Matos, Susana Domingues, Marisa Bedir, Helen Stewart, Timothy Chevassut, Antony W. Oliver, Cecília M. Arraiano, Sarah F. Newbury
    Abstract:

    DIS3 (defective in sister chromatid joining) is the catalytic subunit of the exosome, a protein complex involved in the 3'-5' degradation of RNAs. DIS3 is a highly conserved exoribonuclease, also known as Rrp44. Global sequencing studies have identified DIS3 as being mutated in a range of cancers, with a considerable incidence in multiple myeloma. In this work, we have identified two protein-coding isoforms of DIS3. Both isoforms are functionally relevant and result from alternative splicing. They differ from each other in the size of their N-Terminal Pin (PilT N-Terminal) domain, which has been shown to have endoribonuclease activity and tether DIS3 to the exosome. Isoform 1 encodes a full-length Pin domain, whereas the Pin domain of isoform 2 is shorter and is missing a segment with conserved amino acids. We have carried out biochemical activity assays on both isoforms of full-length DIS3 and the isolated Pin domains. We find that isoform 2, despite missing part of the Pin domain, has greater endonuclease activity compared with isoform 1. Examination of the available structural information allows us to provide a hypothesis to explain this altered behaviour. Our results also show that multiple myeloma patient cells and all cancer cell lines tested have higher levels of isoform 1 compared with isoform 2, whereas acute myeloid leukaemia and chronic myelomonocytic leukaemia patient cells and samples from healthy donors have similar levels of isoforms 1 and 2. Taken together, our data indicate that significant changes in the ratios of the two isoforms could be symptomatic of haematological cancers.