title: Identification of a novel inhibitor of coactivator-associated arginine methyltransferase 1 (CARM1)-mediated methylation of histone H3 Arg-17.
abstract: 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.
authors.affiliation: Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore 560 064, India.
authors.forename: B Ruthrotha
authors.initials: BR
authors.lastname: Selvi
authors.forename: Kiran
authors.initials: K
authors.lastname: Batta
authors.forename: A Hari
authors.initials: AH
authors.lastname: Kishore
authors.forename: Kempegowda
authors.initials: K
authors.lastname: Mantelingu
authors.forename: Radhika A
authors.initials: RA
authors.lastname: Varier
authors.forename: Karanam
authors.initials: K
authors.lastname: Balasubramanyam
authors.forename: Suman Kalyan
authors.initials: SK
authors.lastname: Pradhan
authors.forename: Dipak
authors.initials: D
authors.lastname: Dasgupta
authors.forename: Sokalingam
authors.initials: S
authors.lastname: Sriram
authors.forename: Shipra
authors.initials: S
authors.lastname: Agrawal
authors.forename: Tapas K
authors.initials: TK
authors.lastname: Kundu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001120:Arginine / Q000378:metabolism*; D002460:Cell Line; D004610:Ellagic Acid / Q000737:chemistry / Q000378:metabolism*; D005786:Gene Expression Regulation; D006657:Histones / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D029561:Lythraceae / Q000737:chemistry; D008745:Methylation; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D016297:Mutagenesis, Site-Directed; D011392:Proline / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011484:Protein-Arginine N-Methyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013816:Thermodynamics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: D006657:Histones; D016159:Tumor Suppressor Protein p53; D004610:Ellagic Acid; D001120:Arginine; D011392:Proline; D011484:Protein-Arginine N-Methyltransferases; C119966:coactivator-associated arginine methyltransferase 1