The deletion of the protein phosphatase 1 regulator NIPP1 in testis causes hyperphosphorylation and degradation of the histone methyltransferase EZH2.
J Biol Chem
; 293(47): 18031-18039, 2018 11 23.
Article
em En
| MEDLINE
| ID: mdl-30305391
ABSTRACT
Germ cell proliferation is epigenetically controlled, mainly through DNA methylation and histone modifications. However, the pivotal epigenetic regulators of germ cell self-renewal and differentiation in postnatal testis are still poorly defined. The histone methyltransferase enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of Polycomb repressive complex 2, represses target genes through trimethylation of histone H3 at Lys-27 (H3K27me3), and interacts (in)directly with both protein phosphatase 1 (PP1) and nuclear inhibitor of PP1 (NIPP1). Here, we report that postnatal, testis-specific ablation of NIPP1 in mice results in loss of EZH2 and reduces H3K27me3 levels. Mechanistically, the NIPP1 deletion abrogated PP1-mediated EZH2 dephosphorylation at two cyclin-dependent kinase sites (Thr-345/487), thereby generating hyperphosphorylated EZH2, which is a substrate for proteolytic degradation. Accordingly, alanine mutation of these residues prolonged the half-life of EZH2 in male germ cells. Our study discloses a key role for the PP1NIPP1 holoenzyme in stabilizing EZH2 and maintaining the H3K27me3 mark on genes that are important for germ cell development and spermatogenesis.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Testículo
/
Deleção de Genes
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Peptídeos e Proteínas de Sinalização Intracelular
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Proteína Potenciadora do Homólogo 2 de Zeste
Tipo de estudo:
Etiology_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article