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53BP1 is a reader of the DNA-damage-induced H2A Lys 15 ubiquitin mark

Author

Listed:
  • Amélie Fradet-Turcotte

    (Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue)

  • Marella D. Canny

    (Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue)

  • Cristina Escribano-Díaz

    (Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue)

  • Alexandre Orthwein

    (Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue)

  • Charles C. Y. Leung

    (Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue)

  • Hao Huang

    (Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue)

  • Marie-Claude Landry

    (Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue)

  • Julianne Kitevski-LeBlanc

    (University of Toronto
    University of Toronto
    University of Toronto)

  • Sylvie M. Noordermeer

    (Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue)

  • Frank Sicheri

    (Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue
    University of Toronto
    University of Toronto)

  • Daniel Durocher

    (Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue
    University of Toronto)

Abstract

53BP1 (also called TP53BP1) is a chromatin-associated factor that promotes immunoglobulin class switching and DNA double-strand-break (DSB) repair by non-homologous end joining. To accomplish its function in DNA repair, 53BP1 accumulates at DSB sites downstream of the RNF168 ubiquitin ligase. How ubiquitin recruits 53BP1 to break sites remains unknown as its relocalization involves recognition of histone H4 Lys 20 (H4K20) methylation by its Tudor domain. Here we elucidate how vertebrate 53BP1 is recruited to the chromatin that flanks DSB sites. We show that 53BP1 recognizes mononucleosomes containing dimethylated H4K20 (H4K20me2) and H2A ubiquitinated on Lys 15 (H2AK15ub), the latter being a product of RNF168 action on chromatin. 53BP1 binds to nucleosomes minimally as a dimer using its previously characterized methyl-lysine-binding Tudor domain and a carboxy-terminal extension, termed the ubiquitination-dependent recruitment (UDR) motif, which interacts with the epitope formed by H2AK15ub and its surrounding residues on the H2A tail. 53BP1 is therefore a bivalent histone modification reader that recognizes a histone ‘code’ produced by DSB signalling.

Suggested Citation

  • Amélie Fradet-Turcotte & Marella D. Canny & Cristina Escribano-Díaz & Alexandre Orthwein & Charles C. Y. Leung & Hao Huang & Marie-Claude Landry & Julianne Kitevski-LeBlanc & Sylvie M. Noordermeer & F, 2013. "53BP1 is a reader of the DNA-damage-induced H2A Lys 15 ubiquitin mark," Nature, Nature, vol. 499(7456), pages 50-54, July.
    • Handle: RePEc:nat:nature:v:499:y:2013:i:7456:d:10.1038_nature12318
    DOI: 10.1038/nature12318
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    Cited by:

    1. 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.
    2. Nikolaos Parisis & Pablo D. Dans & Muhammad Jbara & Balveer Singh & Diane Schausi-Tiffoche & Diego Molina-Serrano & Isabelle Brun-Heath & Denisa Hendrychová & Suman Kumar Maity & Diana Buitrago & Rafa, 2023. "Histone H3 serine-57 is a CHK1 substrate whose phosphorylation affects DNA repair," Nature Communications, Nature, vol. 14(1), pages 1-20, 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.

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