Expanded palette of RNA base editors for comprehensive RBP-RNA interactome studies

Hugo C. Medina-Munoz, Eric Kofman, Pratibha Jagannatha, Evan A. Boyle, Tao Yu, Krysten L. Jones, Jasmine R. Mueller, Grace D. Lykins, Andrew T. Doudna, Samuel S. Park, Steven M. Blue, Brodie L. Ranzau, Rahul M. Kohli, Alexis C. Komor and Gene W. Yeo ()
Additional contact information
Hugo C. Medina-Munoz: University of California San Diego
Eric Kofman: University of California San Diego
Pratibha Jagannatha: University of California San Diego
Evan A. Boyle: University of California San Diego
Tao Yu: University of California San Diego
Krysten L. Jones: University of California San Diego
Jasmine R. Mueller: University of California San Diego
Grace D. Lykins: University of California San Diego
Andrew T. Doudna: University of California San Diego
Samuel S. Park: University of California San Diego
Steven M. Blue: University of California San Diego
Brodie L. Ranzau: University of California San Diego
Rahul M. Kohli: University of Pennsylvania
Alexis C. Komor: University of California San Diego
Gene W. Yeo: University of California San Diego

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract RNA binding proteins (RBPs) are key regulators of RNA processing and cellular function. Technologies to discover RNA targets of RBPs such as TRIBE (targets of RNA binding proteins identified by editing) and STAMP (surveying targets by APOBEC1 mediated profiling) utilize fusions of RNA base-editors (rBEs) to RBPs to circumvent the limitations of immunoprecipitation (CLIP)-based methods that require enzymatic digestion and large amounts of input material. To broaden the repertoire of rBEs suitable for editing-based RBP-RNA interaction studies, we have devised experimental and computational assays in a framework called PRINTER (protein-RNA interaction-based triaging of enzymes that edit RNA) to assess over thirty A-to-I and C-to-U rBEs, allowing us to identify rBEs that expand the characterization of binding patterns for both sequence-specific and broad-binding RBPs. We also propose specific rBEs suitable for dual-RBP applications. We show that the choice between single or multiple rBEs to fuse with a given RBP or pair of RBPs hinges on the editing biases of the rBEs and the binding preferences of the RBPs themselves. We believe our study streamlines and enhances the selection of rBEs for the next generation of RBP-RNA target discovery.

Date: 2024
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DOI: 10.1038/s41467-024-45009-4

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