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

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Listed:
  • Jiaxu Wang

    (Hebei University)

  • Zenglin Yuan

    (Shandong University)

  • Yaqi Cui

    (Hebei University
    Beckman Research Institute, City of Hope)

  • Rong Xie

    (Hebei University
    Beckman Research Institute, City of Hope)

  • Guang Yang

    (Beckman Research Institute, City of Hope)

  • Muzaffer A. Kassab

    (Beckman Research Institute, City of Hope)

  • Mengxi Wang

    (Hebei University)

  • Yinliang Ma

    (Hebei University
    Beckman Research Institute, City of Hope)

  • Chen Wu

    (Hebei University)

  • Xiaochun Yu

    (Beckman Research Institute, City of Hope)

  • Xiuhua Liu

    (Hebei University)

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.

Suggested Citation

  • Jiaxu Wang & Zenglin Yuan & Yaqi Cui & Rong Xie & Guang Yang & Muzaffer A. Kassab & Mengxi Wang & Yinliang Ma & Chen Wu & Xiaochun Yu & Xiuhua Liu, 2018. "Molecular basis for the inhibition of the methyl-lysine binding function of 53BP1 by TIRR," Nature Communications, Nature, vol. 9(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05174-9
    DOI: 10.1038/s41467-018-05174-9
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    Cited by:

    1. Susan Kilgas & Aleem Syed & Patrick Toolan-Kerr & Michelle L. Swift & Shrabasti Roychoudhury & Aniruddha Sarkar & Sarah Wilkins & Mikayla Quigley & Anna R. Poetsch & Maria Victoria Botuyan & Gaofeng C, 2024. "NEAT1 modulates the TIRR/53BP1 complex to maintain genome integrity," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    2. Gaofeng Cui & Maria Victoria Botuyan & Pascal Drané & Qi Hu & Benoît Bragantini & James R. Thompson & David J. Schuller & Alexandre Detappe & Michael T. Perfetti & Lindsey I. James & Stephen V. Frye &, 2023. "An autoinhibited state of 53BP1 revealed by small molecule antagonists and protein engineering," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    3. Sameer Bikram Shah & Youhang Li & Shibo Li & Qing Hu & Tong Wu & Yanmeng Shi & Tran Nguyen & Isaac Ive & Linda Shi & Hailong Wang & Xiaohua Wu, 2024. "53BP1 deficiency leads to hyperrecombination using break-induced replication (BIR)," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

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