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000137609 0247_ $$2ISSN$$a0305-1048
000137609 0247_ $$2ISSN$$a1362-4962
000137609 0247_ $$2ISSN$$a1746-8272
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000137609 037__ $$aDKFZ-2018-01489
000137609 041__ $$aeng
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000137609 1001_ $$aParedes, Roberto$$b0
000137609 245__ $$aEVI1 carboxy-terminal phosphorylation is ATM-mediated and sustains transcriptional modulation and self-renewal via enhanced CtBP1 association.
000137609 260__ $$aOxford$$bOxford Univ. Press44364$$c2018
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000137609 520__ $$aThe transcriptional regulator EVI1 has an essential role in early hematopoiesis and development. However, aberrantly high expression of EVI1 has potent oncogenic properties and confers poor prognosis and chemo-resistance in leukemia and solid tumors. To investigate to what extent EVI1 function might be regulated by post-translational modifications we carried out mass spectrometry- and antibody-based analyses and uncovered an ATM-mediated double phosphorylation of EVI1 at the carboxy-terminal S858/S860 SQS motif. In the presence of genotoxic stress EVI1-WT (SQS), but not site mutated EVI1-AQA was able to maintain transcriptional patterns and transformation potency, while under standard conditions carboxy-terminal mutation had no effect. Maintenance of hematopoietic progenitor cell clonogenic potential was profoundly impaired with EVI1-AQA compared with EVI1-WT, in particular in the presence of genotoxic stress. Exploring mechanistic events underlying these observations, we showed that after genotoxic stress EVI1-WT, but not EVI1-AQA increased its level of association with its functionally essential interaction partner CtBP1, implying a role for ATM in regulating EVI1 protein interactions via phosphorylation. This aspect of EVI1 regulation is therapeutically relevant, as chemotherapy-induced genotoxicity might detrimentally sustain EVI1 function via stress response mediated phosphorylation, and ATM-inhibition might be of specific targeted benefit in EVI1-overexpressing malignancies.
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000137609 7001_ $$aSchneider, Marion$$b1
000137609 7001_ $$aStevens, Adam$$b2
000137609 7001_ $$aWhite, Daniel J$$b3
000137609 7001_ $$aWilliamson, Andrew J K$$b4
000137609 7001_ $$aMuter, Joanne$$b5
000137609 7001_ $$aPearson, Stella$$b6
000137609 7001_ $$aKelly, James R$$b7
000137609 7001_ $$aConnors, Kathleen$$b8
000137609 7001_ $$aWiseman, Daniel H$$b9
000137609 7001_ $$aChadwick, John A$$b10
000137609 7001_ $$0P:(DE-He78)3d0bd280b309d8ef615f728f271a8595$$aLöffler, Harald$$b11$$udkfz
000137609 7001_ $$aTeng, Hsiang Ying$$b12
000137609 7001_ $$aLovell, Simon$$b13
000137609 7001_ $$aUnwin, Richard$$b14
000137609 7001_ $$avan de Vrugt, Henri J$$b15
000137609 7001_ $$aSmith, Helen$$b16
000137609 7001_ $$aKustikova, Olga$$b17
000137609 7001_ $$aSchambach, Axel$$b18
000137609 7001_ $$aSomervaille, Tim C P$$b19
000137609 7001_ $$aPierce, Andrew$$b20
000137609 7001_ $$aWhetton, Anthony D$$b21
000137609 7001_ $$aMeyer, Stefan$$b22
000137609 773__ $$0PERI:(DE-600)2205588-5$$a10.1093/nar/gky536$$gVol. 46, no. 15, p. 7662 - 7674$$n15$$p7662 - 7674$$tNucleic acids symposium series$$v46$$x1362-4962$$y2018
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