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Nat Commun. 2018 Jul 12;9(1):2689. doi: 10.1038/s41467-018-05174-9.

Molecular basis for the inhibition of the methyl-lysine binding function of 53BP1 by TIRR.

Author information

1
College of Life Sciences, Hebei University, Baoding, 071000, Hebei, China.
2
State Key Laboratory of Microbial Technology, Shandong University, Jinan, 250100, Shandong, China.
3
Department of Cancer Genetics and Epigenetics, Beckman Research Institute, City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA.
4
Department of Cancer Genetics and Epigenetics, Beckman Research Institute, City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA. xyu@coh.org.
5
College of Life Sciences, Hebei University, Baoding, 071000, Hebei, China. liuxiuhua_2004@163.com.

Abstract

53BP1 performs essential functions in DNA double-strand break (DSB) repair and it was recently reported that Tudor interacting repair regulator (TIRR) negatively regulates 53BP1 during DSB repair. Here, we present the crystal structure of the 53BP1 tandem Tudor domain (TTD) in complex with TIRR. Our results show that three loops from TIRR interact with 53BP1 TTD and mask the methylated lysine-binding pocket in TTD. Thus, TIRR competes with histone H4K20 methylation for 53BP1 binding. We map key interaction residues in 53BP1 TTD and TIRR, whose mutation abolishes complex formation. Moreover, TIRR suppresses the relocation of 53BP1 to DNA lesions and 53BP1-dependent DNA damage repair. Finally, despite the high-sequence homology between TIRR and NUDT16, NUDT16 does not directly interact with 53BP1 due to the absence of key residues required for binding. Taken together, our study provides insights into the molecular mechanism underlying TIRR-mediated suppression of 53BP1-dependent DNA damage repair.

PMID:
30002377
PMCID:
PMC6043480
DOI:
10.1038/s41467-018-05174-9
[Indexed for MEDLINE]
Free PMC Article

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