%0 Journal Article
%A Paredes, Roberto
%A Schneider, Marion
%A Stevens, Adam
%A White, Daniel J
%A Williamson, Andrew J K
%A Muter, Joanne
%A Pearson, Stella
%A Kelly, James R
%A Connors, Kathleen
%A Wiseman, Daniel H
%A Chadwick, John A
%A Löffler, Harald
%A Teng, Hsiang Ying
%A Lovell, Simon
%A Unwin, Richard
%A van de Vrugt, Henri J
%A Smith, Helen
%A Kustikova, Olga
%A Schambach, Axel
%A Somervaille, Tim C P
%A Pierce, Andrew
%A Whetton, Anthony D
%A Meyer, Stefan
%T EVI1 carboxy-terminal phosphorylation is ATM-mediated and sustains transcriptional modulation and self-renewal via enhanced CtBP1 association.
%J Nucleic acids symposium series
%V 46
%N 15
%@ 1362-4962
%C Oxford
%I Oxford Univ. Press44364
%M DKFZ-2018-01489
%P 7662 - 7674
%D 2018
%X 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:29939287
%2 pmc:PMC6125627
%R 10.1093/nar/gky536
%U https://inrepo02.dkfz.de/record/137609