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Title: NIPP1 maintains EZH2 phosphorylation and promoter occupancy at proliferation-related target genes
Authors: Minnebo, Nikki
Goernemann, Janina
O'Connell, Nichole
Van Dessel, Nele
Derua, Rita
Vermunt, Marit Willemijn
Page, Rebecca
Beullens, Monique
Peti, Wolfgang
Van Eynde, Aleyde
Bollen, Mathieu # ×
Issue Date: 1-Jan-2013
Publisher: Oxford University Press
Series Title: Nucleic Acids Research vol:41 issue:2 pages:842-854
Abstract: The histone methyltransferase EZH2 regulates cell proliferation and differentiation by silencing Polycomb group target genes. NIPP1, a nuclear regulator of serine/threonine protein phosphatase 1 (PP1), has been implicated in the regulation of EZH2 occupancy at target loci, but the underlying mechanism is not understood. Here, we demonstrate that the phosphorylation of EZH2 by cyclin-dependent kinases at Thr416 creates a docking site for the ForkHead-associated domain of NIPP1. Recruited NIPP1 enables the net phosphorylation of EZH2 by inhibiting its dephosphorylation by PP1. Accordingly, a NIPP1-binding mutant of EZH2 is hypophosphorylated, and the knockdown of NIPP1 results in a reduced phosphorylation of endogenous EZH2. Conversely, the loss of PP1 is associated with a hyperphosphorylation of EZH2. A genome-wide promoter-binding profiling in HeLa cells revealed that the NIPP1-binding mutant shows a deficient association with about a third of the Polycomb target genes, and these are enriched for functions in proliferation. Our data identify PP1 as an EZH2 phosphatase and demonstrate that the phosphorylation-regulated association of EZH2 with proliferation-related targets depends on associated NIPP1.
URI: 
ISSN: 0305-1048
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Biosignaling & Therapeutics
× corresponding author
# (joint) last author

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