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      Arabidopsis RETINOBLASTOMA RELATED directly regulates DNA damage responses through functions beyond cell cycle control

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          Abstract

          The rapidly proliferating cells in plant meristems must be protected from genome damage. Here, we show that the regulatory role of the Arabidopsis RETINOBLASTOMA RELATED ( RBR) in cell proliferation can be separated from a novel function in safeguarding genome integrity. Upon DNA damage, RBR and its binding partner E2 FA are recruited to heterochromatic γH2 AX‐labelled DNA damage foci in an ATM‐ and ATR‐dependent manner. These γH2 AX‐labelled DNA lesions are more dispersedly occupied by the conserved repair protein, At BRCA1, which can also co‐localise with RBR foci. RBR and At BRCA1 physically interact in vitro and in planta. Genetic interaction between the RBR‐silenced ami RBR and Atbrca1 mutants suggests that RBR and At BRCA1 may function together in maintaining genome integrity. Together with E2 FA, RBR is directly involved in the transcriptional DNA damage response as well as in the cell death pathway that is independent of SOG1, the plant functional analogue of p53. Thus, plant homologs and analogues of major mammalian tumour suppressor proteins form a regulatory network that coordinates cell proliferation with cell and genome integrity.

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          Most cited references74

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          The DNA damage response: ten years after.

          The DNA damage response (DDR), through the action of sensors, transducers, and effectors, orchestrates the appropriate repair of DNA damage and resolution of DNA replication problems, coordinating these processes with ongoing cellular physiology. In the past decade, we have witnessed an explosion in understanding of DNA damage sensing, signaling, and the complex interplay between protein phosphorylation and the ubiquitin pathway employed by the DDR network to execute the response to DNA damage. These findings have important implications for aging and cancer.
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            Glc-TOR signalling leads transcriptome reprogramming and meristem activation

            Meristems encompass stem/progenitor cells that sustain postembryonic growth of all plant organs. How meristems are activated and sustained by nutrient signalling remains enigmatic in photosynthetic plants. Combining chemical manipulations and chemical genetics at the photoautotrophic transition checkpoint, we reveal that shoot photosynthesis-derived glucose drives target-of-rapamycin (TOR) signalling relays through glycolysis and mitochondrial bioenergetics to control root meristem activation, which is decoupled from direct glucose sensing, growth-hormone signalling, and stem-cell maintenance. Surprisingly, glucose-TOR signalling dictates transcriptional reprogramming of remarkable gene sets involved in central and secondary metabolism, cell cycle, transcription, signalling, transport and folding. Systems, cellular and genetic analyses uncover TOR phosphorylation of E2Fa transcription factor for an unconventional activation of S-phase genes, and glucose-signalling defects in e2fa root meristems. Our findings establish pivotal roles of glucose-TOR signalling in unprecedented transcriptional networks wiring central metabolism and biosynthesis for energy and biomass production, and integrating localized stem/progenitor-cell proliferation through inter-organ nutrient coordination to control developmental transition and growth.
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              Molecular mechanisms underlying RB protein function.

              Inactivation of the RB protein is one of the most fundamental events in cancer. Coming to a molecular understanding of its function in normal cells and how it impedes cancer development has been challenging. Historically, the ability of RB to regulate the cell cycle placed it in a central role in proliferative control, and research focused on RB regulation of the E2F family of transcription factors. Remarkably, several recent studies have found additional tumour-suppressor functions of RB, including alternative roles in the cell cycle, maintenance of genome stability and apoptosis. These advances and new structural studies are combining to define the multifunctionality of RB.
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                Author and article information

                Contributors
                beatrix.horvath@rhul.ac.uk
                ben.scheres@wur.nl
                Journal
                EMBO J
                EMBO J
                10.1002/(ISSN)1460-2075
                EMBJ
                embojnl
                The EMBO Journal
                John Wiley and Sons Inc. (Hoboken )
                0261-4189
                1460-2075
                20 March 2017
                02 May 2017
                20 March 2017
                : 36
                : 9 ( doiID: 10.1002/embj.v36.9 )
                : 1261-1278
                Affiliations
                [ 1 ] School of Biological Sciences Centre for Systems and Synthetic BiologyRoyal Holloway, University of London EghamUK
                [ 2 ] Department of Molecular GeneticsUtrecht University UtrechtThe Netherlands
                [ 3 ] Institute of Microbiology CASv.v.i., Laboratory of Cell Reproduction Prague 4Czech Republic
                [ 4 ] Department of Medical Chemistry, Molecular Biology and PathobiochemistrySemmelweis University BudapestHungary
                [ 5 ] Institute of Plant BiologyBiological Research Centre SzegedHungary
                [ 6 ] Department of Plant SciencesWageningen University Research Centre WageningenThe Netherlands
                [ 7 ] Laboratory of Proteomic ResearchBiological Research Centre SzegedHungary
                [ 8 ]Technical Analytical Research Group of HAS BudapestHungary
                Author notes
                [*] [* ] Corresponding author. Tel: +31 317 313734; E‐mail: beatrix.horvath@ 123456rhul.ac.uk

                Corresponding author. Tel: +31 317 481 166; E‐mail: ben.scheres@ 123456wur.nl

                [†]

                These authors contributed equally to this work as first authors

                [‡]

                These authors contributed equally to this work as senior authors

                Author information
                http://orcid.org/0000-0002-6083-992X
                http://orcid.org/0000-0002-9233-0773
                http://orcid.org/0000-0003-0640-6098
                http://orcid.org/0000-0002-0258-704X
                http://orcid.org/0000-0001-5400-9578
                Article
                EMBJ201694561
                10.15252/embj.201694561
                5412863
                28320736
                a12b4032-48a5-494c-8218-bb2aea835e90
                © 2017 The Authors. Published under the terms of the CC BY 4.0 license

                This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 19 April 2016
                : 20 February 2017
                : 23 February 2017
                Page count
                Figures: 15, Tables: 1, Pages: 18, Words: 14326
                Funding
                Funded by: Marie‐Curie IEF
                Award ID: FP7‐PEOPLE‐2012‐IEF 330789
                Award ID: FP7‐PEOPLE‐2012‐IEF 330713
                Funded by: Netherlands Organization for Scientific Research
                Funded by: Utrecht University
                Award ID: CBSG2/NCSB
                Funded by: Biotechnology and Biological Sciences Research Council (BBSRC)
                Award ID: BB/M025047/1
                Funded by: Grant Agency of the Czech Republic
                Award ID: 15‐11657S P501
                Funded by: Hungarian Academy
                Award ID: OTKA 107838
                Funded by: ERA‐CAPS
                Award ID: 2013/15548/ALW
                Funded by: Ministry for National Economy (Hungary)
                Award ID: GINOP‐2.3.2‐15‐2016‐00001
                Award ID: GINOP‐2.3.2‐15‐2016‐00032
                Award ID: GINOP‐2.3.2‐15‐2016‐00020
                Funded by: National Science Foundation (NSF)
                Award ID: BB/M025047/1
                Funded by: Campus Hungary
                Award ID: TÁMOP‐4.2.4B/2‐11/1‐2012‐0001
                Categories
                Article
                Articles
                Custom metadata
                2.0
                embj201694561
                2 May 2017
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.0.9 mode:remove_FC converted:02.05.2017

                Molecular biology
                arabidopsis,brca1,dna damage response,e2fa,retinoblastoma related,cell cycle,dna replication, repair & recombination,plant biology

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