Identification of a Novel Inhibitor of Coactivator-associated Arginine Methyltransferase 1 (CARM1)-mediated Methylation of Histone H3 Arg-17

• Published in: The Journal of biological chemistry Vol. 285; no. 10; pp. 7143 - 7152
• Main Authors: Selvi, B. Ruthrotha, Batta, Kiran, Kishore, A. Hari, Mantelingu, Kempegowda, Varier, Radhika A., Balasubramanyam, Karanam, Pradhan, Suman Kalyan, Dasgupta, Dipak, Sriram, Sokalingam, Agrawal, Shipra, Kundu, Tapas K.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.03.2010; American Society for Biochemistry and Molecular Biology
• Subjects: Amino Acid Sequence; Animals; Arginine - metabolism; Arginine Methylation; CARM1; Cell Line; Chromatin; Chromatin Histone Modification; Coactivator Transcription; Ellagic Acid - chemistry; Ellagic Acid - metabolism; Enzyme Inhibitors; Epigenetics; Gene Expression; Gene Expression Regulation; Gene Regulation; Histones - chemistry; Histones - genetics; Histones - metabolism; Humans; Lythraceae - chemistry; Methylation; Models, Molecular; Molecular Sequence Data; Molecular Structure; Mutagenesis, Site-Directed; p53; Proline - metabolism; Protein Structure, Tertiary; Protein-Arginine N-Methyltransferases - antagonists & inhibitors; Protein-Arginine N-Methyltransferases - chemistry; Protein-Arginine N-Methyltransferases - genetics; Protein-Arginine N-Methyltransferases - metabolism; TBBD; Thermodynamics; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Xenopus laevis; Chromatin Histone Modification; Chromatin; Enzyme Inhibitors; Gene Expression; Coactivator Transcription; Arginine Methylation; CARM1; TBBD; Epigenetics; p53
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M109.063933

Methylation of the arginine residues of histones by methyltransferases has important consequences for chromatin structure and gene regulation; however, the molecular mechanism(s) of methyltransferase regulation is still unclear, as is the biological significance of methylation at particular arginine residues. Here, we report a novel specific inhibitor of coactivator-associated arginine methyltransferase 1 (CARM1; also known as PRMT4) that selectively inhibits methylation at arginine 17 of histone H3 (H3R17). Remarkably, this plant-derived inhibitor, called TBBD (ellagic acid), binds to the substrate (histone) preferentially at the signature motif, “KAPRK,” where the proline residue (Pro-16) plays a critical role for interaction and subsequent enzyme inhibition. In a promoter-specific context, inhibition of H3R17 methylation represses expression of p21, a p53-responsive gene, thus implicating a possible role for H3 Arg-17 methylation in tumor suppressor function. These data establish TBBD as a novel specific inhibitor of arginine methylation and demonstrate substrate sequence-directed inhibition of enzyme activity by a small molecule and its physiological consequence.