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    EVI1 carboxy-terminal phosphorylation is ATM-mediated and sustains transcriptional modulation and self-renewal via enhanced CtBP1 association.

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    Authors
    Paredes, Roberto
    Schneider, Marion
    Stevens, A
    White, Daniel J
    Williamson, Andrew J K
    Muter, Joanne
    Pearson, Stella
    Kelly, James R
    Connors, Kathleen
    Wiseman, Daniel H
    Chadwick, John A
    Löffler, H
    Teng, Hsiang Ying
    Lovell, S
    Unwin, Richard D
    van de Vrugt, H
    Smith, H
    Kustikova, O
    Schambach, A
    Somervaille, Tim C P
    Pierce, Andrew
    Whetton, Anthony D
    Meyer, Stefan
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    Affiliation
    Stem Cell and Leukaemia Proteomics Laboratory, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Palatine Road, Manchester M20 3LI, UK
    Issue Date
    2018-06-25
    
    Metadata
    Show full item record
    Abstract
    The transcriptional regulator EVI1 has an essential role in early hematopoiesis and development. However, aberrantly high expression of EVI1 has potent oncogenic properties and confers poor prognosis and chemo-resistance in leukemia and solid tumors. To investigate to what extent EVI1 function might be regulated by post-translational modifications we carried out mass spectrometry- and antibody-based analyses and uncovered an ATM-mediated double phosphorylation of EVI1 at the carboxy-terminal S858/S860 SQS motif. In the presence of genotoxic stress EVI1-WT (SQS), but not site mutated EVI1-AQA was able to maintain transcriptional patterns and transformation potency, while under standard conditions carboxy-terminal mutation had no effect. Maintenance of hematopoietic progenitor cell clonogenic potential was profoundly impaired with EVI1-AQA compared with EVI1-WT, in particular in the presence of genotoxic stress. Exploring mechanistic events underlying these observations, we showed that after genotoxic stress EVI1-WT, but not EVI1-AQA increased its level of association with its functionally essential interaction partner CtBP1, implying a role for ATM in regulating EVI1 protein interactions via phosphorylation. This aspect of EVI1 regulation is therapeutically relevant, as chemotherapy-induced genotoxicity might detrimentally sustain EVI1 function via stress response mediated phosphorylation, and ATM-inhibition might be of specific targeted benefit in EVI1-overexpressing malignancies.
    Citation
    EVI1 carboxy-terminal phosphorylation is ATM-mediated and sustains transcriptional modulation and self-renewal via enhanced CtBP1 association. 2018, Nucleic Acids Res
    Journal
    Nucleic Acids Research
    URI
    http://hdl.handle.net/10541/621146
    DOI
    10.1093/nar/gky536
    PubMed ID
    29939287
    Type
    Article
    Language
    en
    ISSN
    1362-4962
    ae974a485f413a2113503eed53cd6c53
    10.1093/nar/gky536
    Scopus Count
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    All Christie Publications

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