TY  - JOUR
AU  - Paredes, Roberto
AU  - Schneider, Marion
AU  - Stevens, Adam
AU  - White, Daniel J
AU  - Williamson, Andrew J K
AU  - Muter, Joanne
AU  - Pearson, Stella
AU  - Kelly, James R
AU  - Connors, Kathleen
AU  - Wiseman, Daniel H
AU  - Chadwick, John A
AU  - Löffler, Harald
AU  - Teng, Hsiang Ying
AU  - Lovell, Simon
AU  - Unwin, Richard
AU  - van de Vrugt, Henri J
AU  - Smith, Helen
AU  - Kustikova, Olga
AU  - Schambach, Axel
AU  - Somervaille, Tim C P
AU  - Pierce, Andrew
AU  - Whetton, Anthony D
AU  - Meyer, Stefan
TI  - EVI1 carboxy-terminal phosphorylation is ATM-mediated and sustains transcriptional modulation and self-renewal via enhanced CtBP1 association.
JO  - Nucleic acids symposium series
VL  - 46
IS  - 15
SN  - 1362-4962
CY  - Oxford
PB  - Oxford Univ. Press44364
M1  - DKFZ-2018-01489
SP  - 7662 - 7674
PY  - 2018
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:29939287
C2  - pmc:PMC6125627
DO  - DOI:10.1093/nar/gky536
UR  - https://inrepo02.dkfz.de/record/137609
ER  -