Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Amino Acid Substitution
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Binding Sites
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Carrier Proteins / chemistry*
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Crystallography, X-Ray
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DNA Breaks, Double-Stranded
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DNA Repair
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Histones / chemistry
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Histones / metabolism
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Humans
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Models, Molecular
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Mutagenesis, Site-Directed
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Protein Binding
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Protein Engineering
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Protein Interaction Maps
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Protein Processing, Post-Translational
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Pyrophosphatases / chemistry
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Pyrophosphatases / genetics
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Pyrophosphatases / metabolism
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RNA-Binding Proteins / chemistry*
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RNA-Binding Proteins / genetics
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RNA-Binding Proteins / metabolism*
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Tumor Suppressor p53-Binding Protein 1 / chemistry*
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Tumor Suppressor p53-Binding Protein 1 / genetics
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Tumor Suppressor p53-Binding Protein 1 / metabolism*
Substances
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Carrier Proteins
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Histones
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NUDT16L1 protein, human
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RNA-Binding Proteins
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TP53BP1 protein, human
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Tumor Suppressor p53-Binding Protein 1
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Nudt16 protein, human
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Pyrophosphatases