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Nat Commun. 2018 May 29;9(1):2123. doi: 10.1038/s41467-018-04557-2.

Structural basis for recognition of 53BP1 tandem Tudor domain by TIRR.

Author information

1
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
2
University of Chinese Academy of Sciences, Beijing, 100049, China.
3
Department of Cancer Biology, Cleveland Clinic Lerner Research Institute, Cleveland, 44195, OH, USA.
4
Department of Cancer Biology, Cleveland Clinic Lerner Research Institute, Cleveland, 44195, OH, USA. gongz@ccf.org.
5
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China. zhouzh@sun5.ibp.ac.cn.
6
University of Chinese Academy of Sciences, Beijing, 100049, China. zhouzh@sun5.ibp.ac.cn.

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.

PMID:
29844495
PMCID:
PMC5974088
DOI:
10.1038/s41467-018-04557-2
[Indexed for MEDLINE]
Free PMC Article

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