TY - JOUR T1 - Pharmacological inhibition of PRMT7 links arginine monomethylation to the cellular stress responses JF - bioRxiv DO - 10.1101/503136 SP - 503136 AU - Magdalena M Szewczyk AU - Yoshinori Ishikawa AU - Shawna Organ AU - Nozomu Sakai AU - Fengling Li AU - Suzanne Ackloo AU - Mohammad Eram AU - David Dilworth AU - Hideto Fukushi AU - Rachel Harding AU - Carlo C dela Seña AU - Tsukasa Sugo AU - Kozo Hayashi AU - David Macleod AU - Carlos Zepeda AU - Shinji Takagi AU - Rima Al-Awar AU - Stephane Richard AU - Masayuki Takizawa AU - Cheryl H Arrowsmith AU - Masoud Vedadi AU - Peter J Brown AU - Hiroshi Nara AU - Dalia Barsyte-Lovejoy Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/12/21/503136.abstract N2 - 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 resulted in drastically reduced levels of arginine monomethylation of HSP70 family members and other stress-associated proteins. Structural and biochemical analysis revealed that PRMT7-driven in vitro methylation of HSP70 at R469 requires an ATP-bound, open conformation of HSP70. In cells, SGC3027 inhibited methylation of both constitutive and inducible forms of HSP70, and led 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. ER -