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@ARTICLE{Paredes:137609,
      author       = {R. Paredes and M. Schneider and A. Stevens and D. J. White
                      and A. J. K. Williamson and J. Muter and S. Pearson and J.
                      R. Kelly and K. Connors and D. H. Wiseman and J. A. Chadwick
                      and H. Löffler$^*$ and H. Y. Teng and S. Lovell and R.
                      Unwin and H. J. van de Vrugt and H. Smith and O. Kustikova
                      and A. Schambach and T. C. P. Somervaille and A. Pierce and
                      A. D. Whetton and S. Meyer},
      title        = {{EVI}1 carboxy-terminal phosphorylation is {ATM}-mediated
                      and sustains transcriptional modulation and self-renewal via
                      enhanced {C}t{BP}1 association.},
      journal      = {Nucleic acids symposium series},
      volume       = {46},
      number       = {15},
      issn         = {1362-4962},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press44364},
      reportid     = {DKFZ-2018-01489},
      pages        = {7662 - 7674},
      year         = {2018},
      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.},
      cin          = {G330},
      ddc          = {540},
      cid          = {I:(DE-He78)G330-20160331},
      pnm          = {317 - Translational cancer research (POF3-317)},
      pid          = {G:(DE-HGF)POF3-317},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:29939287},
      pmc          = {pmc:PMC6125627},
      doi          = {10.1093/nar/gky536},
      url          = {https://inrepo02.dkfz.de/record/137609},
}