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      PRP-19, a conserved pre-mRNA processing factor and E3 ubiquitin ligase, inhibits the nuclear accumulation of GLP-1/Notch intracellular domain

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          ABSTRACT

          The Notch signalling pathway is a conserved and widespread signalling paradigm, and its misregulation has been implicated in numerous disorders, including cancer. The output of Notch signalling depends on the nuclear accumulation of the Notch receptor intracellular domain (ICD). Using the Caenorhabditis elegans germline, where GLP-1/Notch-mediated signalling is essential for maintaining stem cells, we monitored GLP-1 in vivo. We found that the nuclear enrichment of GLP-1 ICD is dynamic: while the ICD is enriched in germ cell nuclei during larval development, it is depleted from the nuclei in adult germlines. We found that this pattern depends on the ubiquitin proteolytic system and the splicing machinery and, identified the splicing factor PRP-19 as a candidate E3 ubiquitin ligase required for the nuclear depletion of GLP-1 ICD.

          Abstract

          Summary: GFP tagging of endogenous GLP-1/Notch revealed life stage-specific differences in the nuclear accumulation of GLP-1 intracellular domain, which are mediated by the ubiquitin-proteolytic system and the splicing factor/E3 ubiquitin ligase PRP-19.

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          Most cited references 68

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          BEDTools: a flexible suite of utilities for comparing genomic features

          Motivation: Testing for correlations between different sets of genomic features is a fundamental task in genomics research. However, searching for overlaps between features with existing web-based methods is complicated by the massive datasets that are routinely produced with current sequencing technologies. Fast and flexible tools are therefore required to ask complex questions of these data in an efficient manner. Results: This article introduces a new software suite for the comparison, manipulation and annotation of genomic features in Browser Extensible Data (BED) and General Feature Format (GFF) format. BEDTools also supports the comparison of sequence alignments in BAM format to both BED and GFF features. The tools are extremely efficient and allow the user to compare large datasets (e.g. next-generation sequencing data) with both public and custom genome annotation tracks. BEDTools can be combined with one another as well as with standard UNIX commands, thus facilitating routine genomics tasks as well as pipelines that can quickly answer intricate questions of large genomic datasets. Availability and implementation: BEDTools was written in C++. Source code and a comprehensive user manual are freely available at http://code.google.com/p/bedtools Contact: aaronquinlan@gmail.com; imh4y@virginia.edu Supplementary information: Supplementary data are available at Bioinformatics online.
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            The genetics of Caenorhabditis elegans.

            Methods are described for the isolation, complementation and mapping of mutants of Caenorhabditis elegans, a small free-living nematode worm. About 300 EMS-induced mutants affecting behavior and morphology have been characterized and about one hundred genes have been defined. Mutations in 77 of these alter the movement of the animal. Estimates of the induced mutation frequency of both the visible mutants and X chromosome lethals suggests that, just as in Drosophila, the genetic units in C. elegans are large.
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              UniProt: the universal protein knowledgebase

                (2016)
              The UniProt knowledgebase is a large resource of protein sequences and associated detailed annotation. The database contains over 60 million sequences, of which over half a million sequences have been curated by experts who critically review experimental and predicted data for each protein. The remainder are automatically annotated based on rule systems that rely on the expert curated knowledge. Since our last update in 2014, we have more than doubled the number of reference proteomes to 5631, giving a greater coverage of taxonomic diversity. We implemented a pipeline to remove redundant highly similar proteomes that were causing excessive redundancy in UniProt. The initial run of this pipeline reduced the number of sequences in UniProt by 47 million. For our users interested in the accessory proteomes, we have made available sets of pan proteome sequences that cover the diversity of sequences for each species that is found in its strains and sub-strains. To help interpretation of genomic variants, we provide tracks of detailed protein information for the major genome browsers. We provide a SPARQL endpoint that allows complex queries of the more than 22 billion triples of data in UniProt (http://sparql.uniprot.org/). UniProt resources can be accessed via the website at http://www.uniprot.org/.
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                Author and article information

                Affiliations
                [1 ]Friedrich Miescher Institute for Biomedical Research , Maulbeerstrasse 66, 4058 Basel, Switzerland
                [2 ]University of Basel , Petersplatz 1, 4001 Basel, Switzerland
                [3 ]Cell Cycle and Development, Institut Jacques Monod, UMR7592 CNRS - Université Paris Diderot, Sorbonne Paris Cité , F-75013 Paris, France
                [4 ]Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo , 0316 Oslo, Norway
                [5 ]Sorbonne Université, CNRS, Institut de Biologie Paris-Seine (IBPS) , Developmental Biology Laboratory, UMR 7622, F-75005 Paris, France
                [6 ]Institute of Bioorganic Chemistry, Polish Academy of Sciences , Noskowskiego 12/14, 61-704 Poznan, Poland
                Author notes
                Journal
                Biol Open
                Biol Open
                bio
                biolopen
                Biology Open
                The Company of Biologists Ltd
                2046-6390
                15 July 2018
                15 July 2018
                15 July 2018
                : 7
                : 7
                BIO034066
                10.1242/bio.034066
                6078339
                30012553
                © 2018. Published by The Company of Biologists Ltd

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

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                Funding
                Funded by: European Cooperation in Science and Technology, http://dx.doi.org/10.13039/501100000921;
                Award ID: C15.0038
                Funded by: National Science Centre, http://dx.doi.org/10.13039/501100004442;
                Award ID: 2015/19/B/NZ3/02412
                Funded by: EMBO, http://dx.doi.org/10.13039/100004410;
                Funded by: Foundation for Polish Science, http://dx.doi.org/10.13039/501100001870;
                Award ID: TEAM/2016-2/11
                Funded by: Novartis Research Foundation;
                Funded by: Fondation pour la Recherche Médicale;
                Award ID: DEQ20140329538
                Funded by: Labex, http://dx.doi.org/10.13039/501100004100;
                Award ID: ANR-11-LABX-0071
                Funded by: French National Research Agency, http://dx.doi.org/10.13039/501100001665;
                Award ID: ANR-11-IDEX-0005-01
                Categories
                Research Article

                Life sciences

                glp-1, caenorhabditis elegans, notch, prp-19, splicing, ubiquitin ligase

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