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TIRR regulates 53BP1 by masking its histone methyl-lysine binding function

Author

Listed:
  • Pascal Drané

    (Dana-Farber Cancer Institute)

  • Marie-Eve Brault

    (Dana-Farber Cancer Institute)

  • Gaofeng Cui

    (Mayo Clinic)

  • Khyati Meghani

    (Dana-Farber Cancer Institute)

  • Shweta Chaubey

    (Dana-Farber Cancer Institute)

  • Alexandre Detappe

    (Dana-Farber Cancer Institute)

  • Nishita Parnandi

    (Dana-Farber Cancer Institute)

  • Yizhou He

    (Dana-Farber Cancer Institute)

  • Xiao-Feng Zheng

    (Dana-Farber Cancer Institute)

  • Maria Victoria Botuyan

    (Mayo Clinic)

  • Alkmini Kalousi

    (Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC))

  • William T. Yewdell

    (Immunology Program, Memorial Sloan-Kettering Cancer Center, Gerstner Sloan-Kettering Graduate School)

  • Christian Münch

    (Harvard Medical School
    † Present address: Institute of Biochemistry II, Goethe University School of Medicine, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.)

  • J. Wade Harper

    (Harvard Medical School)

  • Jayanta Chaudhuri

    (Immunology Program, Memorial Sloan-Kettering Cancer Center, Gerstner Sloan-Kettering Graduate School
    Immunology and Microbial Pathogenesis Program, Weill-Cornell Medical School)

  • Evi Soutoglou

    (Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC))

  • Georges Mer

    (Mayo Clinic)

  • Dipanjan Chowdhury

    (Dana-Farber Cancer Institute
    Harvard Medical School
    Broad Institute of Harvard and MIT)

Abstract

P53-binding protein 1 (53BP1) is a multi-functional double-strand break repair protein that is essential for class switch recombination in B lymphocytes and for sensitizing BRCA1-deficient tumours to poly-ADP-ribose polymerase-1 (PARP) inhibitors. Central to all 53BP1 activities is its recruitment to double-strand breaks via the interaction of the tandem Tudor domain with dimethylated lysine 20 of histone H4 (H4K20me2). Here we identify an uncharacterized protein, Tudor interacting repair regulator (TIRR), that directly binds the tandem Tudor domain and masks its H4K20me2 binding motif. Upon DNA damage, the protein kinase ataxia-telangiectasia mutated (ATM) phosphorylates 53BP1 and recruits RAP1-interacting factor 1 (RIF1) to dissociate the 53BP1–TIRR complex. However, overexpression of TIRR impedes 53BP1 function by blocking its localization to double-strand breaks. Depletion of TIRR destabilizes 53BP1 in the nuclear-soluble fraction and alters the double-strand break-induced protein complex centring 53BP1. These findings identify TIRR as a new factor that influences double-strand break repair using a unique mechanism of masking the histone methyl-lysine binding function of 53BP1.

Suggested Citation

  • Pascal Drané & Marie-Eve Brault & Gaofeng Cui & Khyati Meghani & Shweta Chaubey & Alexandre Detappe & Nishita Parnandi & Yizhou He & Xiao-Feng Zheng & Maria Victoria Botuyan & Alkmini Kalousi & Willia, 2017. "TIRR regulates 53BP1 by masking its histone methyl-lysine binding function," Nature, Nature, vol. 543(7644), pages 211-216, March.
    • Handle: RePEc:nat:nature:v:543:y:2017:i:7644:d:10.1038_nature21358
    DOI: 10.1038/nature21358
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    Citations

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    Cited by:

    1. 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.
    2. Yajie Sun & Jeffrey Patterson-Fortin & Sen Han & Zhe Li & Zuzanna Nowicka & Yuna Hirohashi & Susan Kilgas & Jae Kyo Yi & Alexander Spektor & Wojciech Fendler & Panagiotis A. Konstantinopoulos & Dipanj, 2024. "53BP1 loss elicits cGAS-STING-dependent antitumor immunity in ovarian and pancreatic cancer," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    3. Jian Ma & Yingke Zhou & Penglin Pan & Haixin Yu & Zixi Wang & Lei Lily Li & Bing Wang & Yuqian Yan & Yunqian Pan & Qi Ye & Tianjie Liu & Xiaoyu Feng & Shan Xu & Ke Wang & Xinyang Wang & Yanlin Jian & , 2023. "TRABID overexpression enables synthetic lethality to PARP inhibitor via prolonging 53BP1 retention at double-strand breaks," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    4. 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.

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