Visit our Expo - Redox and Inflammation signaling 2012

Targeting of Polycomb repressive complexes by the moonlighting protein NIPP1
Mathieu Bollen
Division of Biochemistry, Faculty of Medicine, Catholic University of Leuven, B-3000
Leuven, Belgium. E-mail: Mathieu.Bollen@med.kuleuven.be
NIPP1 is a nuclear protein that is ubiquitously expressed in metazoans and plants. The
knockout of NIPP1 in mice is embryonic lethal before gastrulation and NIPP1-/- cell lines are
not viable. NIPP1 interacts in vivo with a protein kinase (MELK), a protein phosphatase
(PP1), two pre-mRNA splicing factors (CDC5L, SAP155) and two transcriptional repressors
(EED, EZH2). We previously reported that NIPP1 is associated with storage sites for splicing
factors and is required for a late step of spliceosome assembly. In addition, NIPP1 functions
as a transcriptional repressor by a mechanism that does not require functional interaction sites
for splicing factors, MELK nor PP1, but depends on the presence of EED and EZH2, two core
components of the Polycomb Repressive Complexes 2-4 (PRC2-4). The latter complexes
initiate the heritable repression of genes that are important for development and cell
proliferation, at least in part by the EZH2-mediated trimethylation of histone H3 on Lys27
(H3K27). Consistent with a role for NIPP1 in Polycomb signalling, we found that NIPP1 is
associated with H3K27-trimethylated chromatin and that NIPP1-/- mouse blastocyst
outgrowths and cultured cells with a decreased concentration of NIPP1 are severely deficient
in H3K27 trimethylation, but are normally trimethylated on H3K9. We also show that NIPP1
is a nucleic-acid binding protein and interacts strongly with intron-1 of the MSMB gene,
which encodes the prostatic tumor growth suppressor PSP94. We identified the MSMB gene
as a novel Polycomb target gene and show that the siRNA-mediated knockdown of NIPP1 is
associated with a decreased recruitment of EZH2 to this gene. These findings are consistent
with the notion that NIPP1 is involved in the recruitment of PRC2 to its target genes. Our data
suggest that NIPP1 functions as a moonlighting protein and has independent functions in premRNA
splicing and transcription.
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