Abstract
PRMT6 is a protein arginine methyltransferase that has been implicated in transcriptional regulation, DNA repair, and human immunodeficiency virus pathogenesis. Only few substrates of this enzyme are known and therefore its cellular role is not well understood. To identify in an unbiased manner substrates and potential regulators of PRMT6 we have used a yeast two-hybrid approach. We identified 36 new putative partners for PRMT6 and we validated the interaction in vivo for 7 of them. In addition, using in vitro methylation assay we identified 4 new substrates for PRMT6, extending the involvement of this enzyme to other cellular processes beyond its well-established role in gene expression regulation. Holistic approaches create molecular connections that allow to test functional hypotheses. The assembly of PRMT6 protein network allowed us to formulate functional hypotheses which led to the discovery of new molecular partners for the architectural transcription factor HMGA1a, a known substrate for PRMT6, and to provide evidences for a modulatory role of HMGA1a on the methyltransferase activity of PRMT6.
Highlights
Protein arginine methylation is a post-translational modification (PTM) that has been implicated in a large variety of important cellular functions such as signalling, DNA repair, RNA maturation and nucleocytoplasmic transport, protein protection, ribosomal assembly, and regulation of gene expression [1]
Bioinformatic analyses (DAVID - Database for Annotation, Visualization and Integrated Discovery bioinformatic tools) evidenced that all the identified partners are intracellular, a consistent number (21) has a predominant nuclear localization, which is consistent with Protein Arginine Methyltransferase 6 (PRMT6) localization [5], and that most of them (27) are localized in the cytoplasm with a considerable number (13) associated with intracellular nonhave previously been identified as partners or substrates of PRMT6
Med28 and MTF2 are subunits of macromolecular complexes involved in gene transcription and chromatin epigenetic modulation, activities that have been firmly established for PRMT6 [6,7,8,9]
Summary
Protein arginine methylation is a post-translational modification (PTM) that has been implicated in a large variety of important cellular functions such as signalling, DNA repair, RNA maturation and nucleocytoplasmic transport, protein protection, ribosomal assembly, and regulation of gene expression [1]. A human fetal brain cDNA library expressing Gal4 activation domain fusion proteins was transfected in the yeast strain containing pEG202-PRMT6 for a screening assay.
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