Journal Article

DKFZ-2018-01489

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png EVI1 carboxy-terminal phosphorylation is ATM-mediated and sustains transcriptional modulation and self-renewal via enhanced CtBP1 association.

Paredes, R. ; Schneider, M. ; Stevens, A. ; White, D. J. ; Williamson, A. J. K. ; Muter, J. ; Pearson, S. ; Kelly, J. R. ; Connors, K. ; Wiseman, D. H. ; Chadwick, J. A. ; Löffler, H.DKFZ* ; Teng, H. Y. ; Lovell, S. ; Unwin, R. ; van de Vrugt, H. J. ; Smith, H. ; Kustikova, O. ; Schambach, A. ; Somervaille, T. C. P. ; Pierce, A. ; Whetton, A. D. ; Meyer, S.

2018
Oxford Univ. Press44364 Oxford

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Please use a persistent id in citations: doi:10.1093/nar/gky536

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.

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Contributing Institute(s):

1. KKE Molekulare Hämatologie/Onkologie (G330)

Research Program(s):

1. 317 - Translational cancer research (POF3-317) (POF3-317)

Appears in the scientific report 2018

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Database coverage:
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