Systematic profiling of conditional degron tag technologies for target validation studies

Daniel P. Bondeson, Zachary Mullin-Bernstein, Sydney Oliver, Thomas A. Skipper, Thomas C. Atack, Nolan Bick, Meilani Ching, Andrew A. Guirguis, Jason Kwon, Carly Langan, Dylan Millson, Brenton R. Paolella, Kevin Tran, Sarah J. Wie, Francisca Vazquez, Zuzana Tothova, Todd R. Golub, William R. Sellers and Alessandra Ianari ()
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Daniel P. Bondeson: The Broad Institute of MIT and Harvard
Zachary Mullin-Bernstein: The Broad Institute of MIT and Harvard
Sydney Oliver: The Broad Institute of MIT and Harvard
Thomas A. Skipper: The Broad Institute of MIT and Harvard
Thomas C. Atack: The Broad Institute of MIT and Harvard
Nolan Bick: The Broad Institute of MIT and Harvard
Meilani Ching: The Broad Institute of MIT and Harvard
Andrew A. Guirguis: The Broad Institute of MIT and Harvard
Jason Kwon: The Broad Institute of MIT and Harvard
Carly Langan: The Broad Institute of MIT and Harvard
Dylan Millson: The Broad Institute of MIT and Harvard
Brenton R. Paolella: The Broad Institute of MIT and Harvard
Kevin Tran: Peter MacCallum Cancer Centre
Sarah J. Wie: The Broad Institute of MIT and Harvard
Francisca Vazquez: The Broad Institute of MIT and Harvard
Zuzana Tothova: The Broad Institute of MIT and Harvard
Todd R. Golub: The Broad Institute of MIT and Harvard
William R. Sellers: The Broad Institute of MIT and Harvard
Alessandra Ianari: The Broad Institute of MIT and Harvard

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: Abstract Conditional degron tags (CDTs) are a powerful tool for target validation that combines the kinetics and reversible action of pharmacological agents with the generalizability of genetic manipulation. However, successful design of a CDT fusion protein often requires a prolonged, ad hoc cycle of construct design, failure, and re-design. To address this limitation, we report here a system to rapidly compare the activity of five unique CDTs: AID/AID2, IKZF3d, dTAG, HaloTag, and SMASh. We demonstrate the utility of this system against 16 unique protein targets. We find that expression and degradation are highly dependent on the specific CDT, the construct design, and the target. None of the CDTs leads to efficient expression and/or degradation across all targets; however, our systematic approach enables the identification of at least one optimal CDT fusion for each target. To enable the adoption of CDT strategies more broadly, we have made these reagents, and a detailed protocol, available as a community resource.

Date: 2022
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DOI: 10.1038/s41467-022-33246-4

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