Abstract
KRAB-associated protein 1 (KAP1), the transcriptional corepressor of Kruppel-associated box zinc finger proteins (KRAB-ZFPs), is subjected to multiple post-translational modifications that are involved in fine-tuning of the multiple biological functions of KAP1. In previous papers, we analyzed the KAP1-dependent molecular mechanism of transcriptional repression mediated by ZNF224, a member of the KRAB-ZFP family, and identified the protein arginine methyltransferase PRMT5 as a component of the ZNF224 repression complex. We demonstrated that PRMT5-mediated histone arginine methylation is required to elicit ZNF224 transcriptional repression. In this study, we show that KAP1 interacts with PRMT5 and is a novel substrate for PRMT5 methylation. Also, we present evidence that the methylation of KAP1 arginine residues regulate the KAP1-ZNF224 interaction, thus suggesting that this KAP1 post-translational modification could actively contribute to the regulation of ZNF224-mediated repression.
Highlights
KRAB-associated protein 1 (KAP1) is a well-known transcriptional corepressor of KRAB-ZFPs
We found that the endogenous PRMT5 protein co-precipitated with the exogenously expressed KAP1 (Figure 1a, lower panel), indicating that KAP1 interacts with PRMT5
The recombinant proteins Flag-KAP1 and Flag-ZNF224 were purified from hypomethylayed HEK293 cells and subjected to an in vitro methylation assay using recombinant Myc-PRMT5 and [3H]-AdoMet
Summary
KAP1 is a well-known transcriptional corepressor of KRAB-ZFPs. The N-terminus of KAP1 contains a tripartite motif composed of a Ring finger, two B-box zinc fingers and a coiled-coil (RBCC). KAP1 is subjected to several post-translational modifications, including SUMOylation and phosphorylation [5,6] These modifications, required for the repressive activity and for the recruitment of histone deacetylase complexes and HP1, are crucial to properly regulate the expression of KAP1-target genes in response to different extracellular stimuli [7,8,9]. We identified PRMT5, a type II protein arginine methyltransferase as a novel component of ZNF224 transcriptional repression complex and demonstrated that histone arginine methylation by PRMT5 is necessary for ZNF224-mediated gene repression [11] These findings prompted us to explore the possibility that PRMT5 interacts with KAP1 and the role of PRMT5 on KAP1 methylation
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