Pharmacological inhibition of PRMT7 links arginine monomethylation to the cellular stress response

• Published in: Nature communications Vol. 11; no. 1; pp. 2396 - 15
• Main Authors: Szewczyk, Magdalena M., Ishikawa, Yoshinori, Organ, Shawna, Sakai, Nozomu, Li, Fengling, Halabelian, Levon, Ackloo, Suzanne, Couzens, Amber L., Eram, Mohammad, Dilworth, David, Fukushi, Hideto, Harding, Rachel, dela Seña, Carlo C., Sugo, Tsukasa, Hayashi, Kozo, McLeod, David, Zepeda, Carlos, Aman, Ahmed, Sánchez-Osuna, Maria, Bonneil, Eric, Takagi, Shinji, Al-Awar, Rima, Tyers, Mike, Richard, Stephane, Takizawa, Masayuki, Gingras, Anne-Claude, Arrowsmith, Cheryl H., Vedadi, Masoud, Brown, Peter J., Nara, Hiroshi, Barsyte-Lovejoy, Dalia
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.05.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/2; 13/51; 14/34; 14/35; 14/63; 38/1; 38/109; 38/44; 38/70; 631/154/556; 631/45/607/1172; 631/80/86/2366; 631/92/458/1648; 82/103; 82/58; 82/80; 82/83; Animals; Arginine; Arginine - metabolism; BASIC BIOLOGICAL SCIENCES; Binding sites; Biological activity; Biology; Cancer; Cellular stress response; Competition; DNA damage; Enzymes; Gene Knockdown Techniques; HCT116 Cells; Heat shock; HSP70 Heat-Shock Proteins - metabolism; Hsp70 protein; Humanities and Social Sciences; Humans; Medical research; Methylation; Methylation - drug effects; multidisciplinary; Peptides; Proteasome inhibitors; Protein Processing, Post-Translational - drug effects; Protein-Arginine N-Methyltransferases - antagonists & inhibitors; Protein-Arginine N-Methyltransferases - genetics; Protein-Arginine N-Methyltransferases - metabolism; Proteins; Recombinant Proteins - genetics; Recombinant Proteins - isolation & purification; Recombinant Proteins - metabolism; Science; Science (multidisciplinary); Sf9 Cells; Stress signalling; Stress, Physiological; Target recognition; Target validation; Therapeutic applications; Therapeutic targets; Transferases
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-16271-z

Protein arginine methyltransferases (PRMTs) regulate diverse biological processes and are increasingly being recognized for their potential as drug targets. Here we report the discovery of a potent, selective, and cell-active chemical probe for PRMT7. SGC3027 is a cell permeable prodrug, which in cells is converted to SGC8158, a potent, SAM-competitive PRMT7 inhibitor. Inhibition or knockout of cellular PRMT7 results in drastically reduced levels of arginine monomethylated HSP70 family stress-associated proteins. Structural and biochemical analyses reveal that PRMT7-driven in vitro methylation of HSP70 at R469 requires an ATP-bound, open conformation of HSP70. In cells, SGC3027 inhibits methylation of both constitutive and inducible forms of HSP70, and leads to decreased tolerance for perturbations of proteostasis including heat shock and proteasome inhibitors. These results demonstrate a role for PRMT7 and arginine methylation in stress response. Protein arginine methyltransferases (PRMTs) are increasingly recognized as potential therapeutic targets but PRMT7 remains an understudied member of this enzyme family. Here, the authors develop a chemical probe for PRMT7 and apply it to elucidate the role of PRMT7 in the cellular stress response.