Year: 2018
Type: article
Abstract: P53-binding protein 1 (53BP1) regulates the double-strand break (DSB) repair pathway choice. A recently identified 53BP1-binding protein Tudor-interacting repair regulator (TIRR) modulates the access of 53BP1 to DSBs by masking the H4K20me2 binding surface on 53BP1, but the underlying mechanism remains unclear. Here we report the 1.76-Å crystal structure of TIRR in complex with 53BP1 tandem Tudor domain. We demonstrate that the N-terminal region (residues 10-24) and the L8-loop of TIRR interact with 53BP1 Tudor through three loops (L1, L3, and L1'). TIRR recognition blocks H4K20me2 binding to 53BP1 Tudor and modulates 53BP1 functions in vivo. Structure comparisons identify a TIRR histidine (H106) that is absent from the TIRR homolog Nudt16, but essential for 53BP1 Tudor binding. Remarkably, mutations mimicking TIRR binding modules restore the disrupted binding of Nudt16-53BP1 Tudor. Our studies elucidate the mechanism by which TIRR recognizes 53BP1 Tudor and functions as a cellular inhibitor of the histone methyl-lysine readers.
Source: Nature Communications
Authors: Yaxin Dai, Aili Zhang, Shan Shan, Zihua Gong, Zheng Zhou
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: Ovarian Cancer Research Fund, Salt Science Research Foundation, Ovarian Cancer Research Fund Alliance, National Natural Science Foundation of China, Chinese Academy of Sciences, Ministry of Science and Technology of the People's Republic of China, Novo Nordisk, Institute of Biophysics, Chinese Academy of Sciences, National Cancer Institute
OpenAlex ID: W2807198260