Discovery of cellular substrates of human RNA-decapping enzyme DCP2 using a stapled bicyclic peptide inhibitor. Issue 4 (15th April 2021)

• Record Type: Journal Article
• Authors: Luo, Yang; Schofield, Jeremy A.; Na, Zhenkun; Hann, Tanja; Simon, Matthew D.; Slavoff, Sarah A.
• Is Part Of: Cell chemical biology. Volume 28:Issue 4(2021)
• Page Start: 463
• Page End: 474.e7
• Publication Date: 2021-04-15
• Subjects: DCP2 -- chemical genetics -- RNA decay -- cyclic peptide -- P-bodies; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2020.12.003
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: DCP2 is an RNA-decapping enzyme that controls the stability of human RNAs that encode factors functioning in transcription and the immune response. While >1, 800 human DCP2 substrates have been identified, compensatory expression changes secondary to genetic ablation of DCP2 have complicated a complete mapping of its regulome. Cell-permeable, selective chemical inhibitors of DCP2 could provide a powerful tool to study DCP2 specificity. Here, we report phage display selection of CP21, a bicyclic peptide ligand to DCP2. CP21 has high affinity and selectivity for DCP2 and inhibits DCP2 decapping activity toward selected RNA substrates in human cells. CP21 increases formation of P-bodies, liquid condensates enriched in intermediates of RNA decay, in a manner that resembles the deletion or mutation of DCP2. We used CP21 to identify 76 previously unreported DCP2 substrates. This work demonstrates that DCP2 inhibition can complement genetic approaches to study RNA decay. Graphical abstract: Highlights: Inhibitor discovery by phage display selection of bicyclic peptide library Inhibition of DCP2 activity in cells via disrupted RNA-decapping factor interactions Chemical-genetic identification of DCP2 substrates Abstract : Luo et al. identify and characterize a bicyclic peptide ligand of DCP2. They demonstrate that this agent selectively inhibits cellular DCP2 activity by indirect depletion of DDX6 from the decapping complex. Macrocyclic ligands therefore serve as useful tools to study RNA decay enzyme substrate selectivity.