An autoinhibited state of 53BP1 revealed by small molecule antagonists and protein engineering

Gaofeng Cui, Maria Victoria Botuyan, Pascal Drané, Qi Hu, Benoît Bragantini, James R. Thompson, David J. Schuller, Alexandre Detappe, Michael T. Perfetti, Lindsey I. James, Stephen V. Frye, Dipanjan Chowdhury and Georges Mer ()
Additional contact information
Gaofeng Cui: Mayo Clinic
Maria Victoria Botuyan: Mayo Clinic
Pascal Drané: Dana-Farber Cancer Institute
Qi Hu: Mayo Clinic
Benoît Bragantini: Mayo Clinic
James R. Thompson: University of Minnesota
David J. Schuller: Cornell University
Alexandre Detappe: Institut de Cancérologie Strasbourg Europe
Michael T. Perfetti: University of North Carolina at Chapel Hill
Lindsey I. James: University of North Carolina at Chapel Hill
Stephen V. Frye: University of North Carolina at Chapel Hill
Dipanjan Chowdhury: Dana-Farber Cancer Institute
Georges Mer: Mayo Clinic

Nature Communications, 2023, vol. 14, issue 1, 1-11

Abstract: Abstract The recruitment of 53BP1 to chromatin, mediated by its recognition of histone H4 dimethylated at lysine 20 (H4K20me2), is important for DNA double-strand break repair. Using a series of small molecule antagonists, we demonstrate a conformational equilibrium between an open and a pre-existing lowly populated closed state of 53BP1 in which the H4K20me2 binding surface is buried at the interface between two interacting 53BP1 molecules. In cells, these antagonists inhibit the chromatin recruitment of wild type 53BP1, but do not affect 53BP1 variants unable to access the closed conformation despite preservation of the H4K20me2 binding site. Thus, this inhibition operates by shifting the conformational equilibrium toward the closed state. Our work therefore identifies an auto-associated form of 53BP1—autoinhibited for chromatin binding—that can be stabilized by small molecule ligands encapsulated between two 53BP1 protomers. Such ligands are valuable research tools to study the function of 53BP1 and have the potential to facilitate the development of new drugs for cancer therapy.

Date: 2023
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DOI: 10.1038/s41467-023-41821-6

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