EVI1 carboxy-terminal phosphorylation is ATM-mediated and sustains transcriptional modulation and self-renewal via enhanced CtBP1 association

Research output: Contribution to journalArticle

  • External authors:
  • Roberto Paredes
  • Marion Schneider
  • Daniel White
  • Andrew J.K. Williamson
  • Joanne Muter
  • Stella Pearson
  • James Kelly
  • Kathleen Connors
  • John Chadwick
  • Harald Loffler
  • Hsiang Ying Teng
  • Henri J. Van De Vrugt
  • Helen Smith
  • Olga Kustikova
  • A. Schambach
  • Andrew Pierce
  • Anthony Whetton
  • Stefan Meyer

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.

Bibliographical metadata

Original languageEnglish
Pages (from-to)7662-7674
JournalNucleic acids research
Volume46
Issue number15
Early online date25 Jun 2018
DOIs
Publication statusPublished - 6 Sep 2018

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