EVI1 phosphorylation at S436 regulates interactions with CtBP1 and DNMT3A and promotes self-renewal


Paredes, Roberto, Kelly, James R, Geary, Bethany, Almarzouq, Batool ORCID: 0000-0002-3905-2751, Schneider, Marion, Pearson, Stella, Narayanan, Prakrithi, Williamson, Andrew, Lovell, Simon C, Wiseman, Daniel H et al (show 11 more authors) (2020) EVI1 phosphorylation at S436 regulates interactions with CtBP1 and DNMT3A and promotes self-renewal. CELL DEATH & DISEASE, 11 (10). 878-.

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Abstract

The transcriptional regulator EVI1 has an essential role in early development and haematopoiesis. However, acute myeloid leukaemia (AML) driven by aberrantly high EVI1 expression has very poor prognosis. To investigate the effects of post-translational modifications on EVI1 function, we carried out a mass spectrometry (MS) analysis of EVI1 in AML and detected dynamic phosphorylation at serine 436 (S436). Wild-type EVI1 (EVI1-WT) with S436 available for phosphorylation, but not non-phosphorylatable EVI1-S436A, conferred haematopoietic progenitor cell self-renewal and was associated with significantly higher organised transcriptional patterns. In silico modelling of EVI1-S436 phosphorylation showed reduced affinity to CtBP1, and CtBP1 showed reduced interaction with EVI1-WT compared with EVI1-S436A. The motif harbouring S436 is a target of CDK2 and CDK3 kinases, which interacted with EVI1-WT. The methyltransferase DNMT3A bound preferentially to EVI1-WT compared with EVI1-S436A, and a hypomethylated cell population associated by EVI1-WT expression in murine haematopoietic progenitors is not maintained with EVI1-S436A. These data point to EVI1-S436 phosphorylation directing functional protein interactions for haematopoietic self-renewal. Targeting EVI1-S436 phosphorylation may be of therapeutic benefit when treating EVI1-driven leukaemia.

Item Type: Article
Uncontrolled Keywords: Humans, DNA Modification Methylases, Alcohol Oxidoreductases, Serine, DNA-Binding Proteins, Transcription Factors, Prognosis, DNA Methylation, Phosphorylation, Leukemia, Myeloid, Acute, Cell Self Renewal, MDS1 and EVI1 Complex Locus Protein, DNA (Cytosine-5-)-Methyltransferases, DNA Methyltransferase 3A
Depositing User: Symplectic Admin
Date Deposited: 26 Oct 2020 08:50
Last Modified: 18 Jan 2023 23:26
DOI: 10.1038/s41419-020-03099-0
Open Access URL: http://doi.org/10.1038/s41419-020-03099-0
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3105142
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