Dynamic protein interaction networks such as DNA double-strand break (DSB) signaling are modulated by post-translational modifications. The DNA repair factor 53BP1 is a rare example of a protein whose post-translational modification-binding function can be switched on and off. 53BP1 is recruited to DSBs by recognizing histone lysine methylation within chromatin, an activity directly inhibited by the 53BP1-binding protein TIRR. X-ray crystal structures of TIRR and a designer protein bound to 53BP1 now reveal a unique regulatory mechanism in which an intricate binding area centered on an essential TIRR arginine residue blocks the methylated-chromatin-binding surface of 53BP1. A 53BP1 separation-of-function mutation that abolishes TIRR-mediated regulation in cells renders 53BP1 hyperactive in response to DSBs, highlighting the key inhibitory function of TIRR. This 53BP1 inhibition is relieved by TIRR-interacting RNA molecules, providing proof-of-principle of RNA-triggered 53BP1 recruitment to DSBs.
Nat Struct Mol Biol
591 - 600
Amino Acid Substitution, Binding Sites, Carrier Proteins, Crystallography, X-Ray, DNA Breaks, Double-Stranded, DNA Repair, Histones, Humans, Models, Molecular, Mutagenesis, Site-Directed, Protein Binding, Protein Engineering, Protein Interaction Maps, Protein Processing, Post-Translational, Pyrophosphatases, RNA-Binding Proteins, Tumor Suppressor p53-Binding Protein 1