Pharmacological inhibition of PRMT7 links arginine monomethylation to the cellular stress response
2018
Protein
argininemethyltransferases (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 probefor 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
argininemonomethylation of
HSP70family members and other stress-associated proteins. Structural and biochemical analysis revealed that PRMT7-driven in vitro methylation of
HSP70at 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
proteostasisincluding heat shock and
proteasome inhibitors. These results demonstrate a role for PRMT7 and
argininemethylation in stress response.
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