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      TIAR marks nuclear G2/M transition granules and restricts CDK1 activity under replication stress

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          Abstract

          The G2/M checkpoint coordinates DNA replication with mitosis and thereby prevents chromosome segregation in the presence of unreplicated or damaged DNA. Here, we show that the RNA‐binding protein TIAR is essential for the G2/M checkpoint and that TIAR accumulates in nuclear foci in late G2 and prophase in cells suffering from replication stress. These foci, which we named G2/M transition granules ( GMGs), occur at low levels in normally cycling cells and are strongly induced by replication stress. In addition to replication stress response proteins, GMGs contain factors involved in RNA metabolism as well as CDK1. Depletion of TIAR accelerates mitotic entry and leads to chromosomal instability in response to replication stress, in a manner that can be alleviated by the concomitant depletion of Cdc25B or inhibition of CDK1. Since TIAR retains CDK1 in GMGs and attenuates CDK1 activity, we propose that the assembly of GMGs may represent a so far unrecognized mechanism that contributes to the activation of the G2/M checkpoint in mammalian cells.

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          Most cited references 56

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          Stress granules: the Tao of RNA triage.

          Cytoplasmic RNA structures such as stress granules (SGs) and processing bodies (PBs) are functional byproducts of mRNA metabolism, sharing substrate mRNA, dynamic properties and many proteins, but also housing separate components and performing independent functions. Each can exist independently, but when coordinately induced they are often tethered together in a cytosolic dance. Although both self-assemble in response to stress-induced perturbations in translation, several recent reports reveal novel proteins and RNAs that are components of these structures but also perform other cellular functions. Proteins that mediate splicing, transcription, adhesion, signaling and development are all integrated with SG and PB assembly. Thus, these ephemeral bodies represent more than just the dynamic sorting of mRNA between translation and decay.
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            Phenotypic profiling of the human genome by time-lapse microscopy reveals cell division genes.

            Despite our rapidly growing knowledge about the human genome, we do not know all of the genes required for some of the most basic functions of life. To start to fill this gap we developed a high-throughput phenotypic screening platform combining potent gene silencing by RNA interference, time-lapse microscopy and computational image processing. We carried out a genome-wide phenotypic profiling of each of the approximately 21,000 human protein-coding genes by two-day live imaging of fluorescently labelled chromosomes. Phenotypes were scored quantitatively by computational image processing, which allowed us to identify hundreds of human genes involved in diverse biological functions including cell division, migration and survival. As part of the Mitocheck consortium, this study provides an in-depth analysis of cell division phenotypes and makes the entire high-content data set available as a resource to the community.
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              Alternative pre-mRNA splicing regulation in cancer: pathways and programs unhinged.

              Alternative splicing of mRNA precursors is a nearly ubiquitous and extremely flexible point of gene control in humans. It provides cells with the opportunity to create protein isoforms of differing, even opposing, functions from a single gene. Cancer cells often take advantage of this flexibility to produce proteins that promote growth and survival. Many of the isoforms produced in this manner are developmentally regulated and are preferentially re-expressed in tumors. Emerging insights into this process indicate that pathways that are frequently deregulated in cancer often play important roles in promoting aberrant splicing, which in turn contributes to all aspects of tumor biology.
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                Author and article information

                Contributors
                vlafarga@cnio.es
                georg.stoecklin@medma.uni-heidelberg.de
                Journal
                EMBO Rep
                EMBO Rep
                10.1002/(ISSN)1469-3178
                EMBR
                embor
                EMBO Reports
                John Wiley and Sons Inc. (Hoboken )
                1469-221X
                1469-3178
                11 December 2018
                January 2019
                11 December 2018
                : 20
                : 1 ( doiID: 10.1002/embr.v20.1 )
                Affiliations
                [ 1 ] German Cancer Research Center (DKFZ) Heidelberg Germany
                [ 2 ] Center for Molecular Biology of Heidelberg University (ZMBH) DKFZ‐ZMBH Alliance Heidelberg Germany
                [ 3 ] Spanish National Cancer Research Centre (CNIO) Madrid Spain
                [ 4 ] Division of Biochemistry Center for Biomedicine and Medical Technology Mannheim (CBTM) Medical Faculty Mannheim Heidelberg University Mannheim Germany
                [ 5 ] CellNetworks Excellence Cluster Heidelberg University Heidelberg Germany
                [ 6 ] Department of Cellular and Molecular Medicine Center for Chromosome Stability and Center for Healthy Aging University of Copenhagen Copenhagen Denmark
                [ 7 ] Science for Life Laboratory Division of Genome Biology Department of Medical Biochemistry and Biophysics Karolinska Institutet Stockholm Sweden
                [ 8 ]Present address: Institute for Genetics University of Bonn Bonn Germany
                Author notes
                [* ] Corresponding author. Tel: +34 917328000; E‐mail: vlafarga@ 123456cnio.es

                Corresponding author. Tel: +49 621 383 71444; E‐mail: georg.stoecklin@ 123456medma.uni-heidelberg.de

                Article
                EMBR201846224
                10.15252/embr.201846224
                6322364
                30538118
                © 2018 The Authors. Published under the terms of the CC BY 4.0 license

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 12, Tables: 0, Pages: 16, Words: 12317
                Product
                Funding
                Funded by: EC|FP7|FP7 People: Marie‐Curie Actions PEOPLE
                Award ID: 300384
                Funded by: Hartmut Hoffmann‐Berling International Graduate School of Molecular and Cellular Biology
                Funded by: Deutsche Krebshilfe
                Award ID: 111219
                Funded by: Deutsche Forschungsgemeinschaft
                Award ID: SFB 1036/TP07
                Categories
                Article
                Articles
                Custom metadata
                2.0
                embr201846224
                January 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.5.4 mode:remove_FC converted:07.01.2019

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