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Methylated lysine 79 of histone H3 targets 53BP1 to DNA double-strand breaks

Author

Listed:
  • Yentram Huyen

    (Wistar Institute
    University of Pennsylvania)

  • Omar Zgheib

    (Wistar Institute
    University of Pennsylvania)

  • Richard A. DiTullio Jr

    (Wistar Institute
    University of Pennsylvania)

  • Vassilis G. Gorgoulis

    (Wistar Institute
    University of Athens)

  • Panayotis Zacharatos

    (Wistar Institute
    University of Athens)

  • Tom J. Petty

    (Wistar Institute
    University of Pennsylvania)

  • Emily A. Sheston

    (Wistar Institute)

  • Hestia S. Mellert

    (Wistar Institute)

  • Elena S. Stavridi

    (Wistar Institute)

  • Thanos D. Halazonetis

    (Wistar Institute
    University of Pennsylvania)

Abstract

The mechanisms by which eukaryotic cells sense DNA double-strand breaks (DSBs) in order to initiate checkpoint responses are poorly understood. 53BP1 is a conserved checkpoint protein with properties of a DNA DSB sensor1,2,3,4,5. Here, we solved the structure of the domain of 53BP1 that recruits it to sites of DSBs. This domain consists of two tandem tudor folds with a deep pocket at their interface formed by residues conserved in the budding yeast Rad9 and fission yeast Rhp9/Crb2 orthologues. In vitro, the 53BP1 tandem tudor domain bound histone H3 methylated on Lys 79 using residues that form the walls of the pocket; these residues were also required for recruitment of 53BP1 to DSBs. Suppression of DOT1L, the enzyme that methylates Lys 79 of histone H3, also inhibited recruitment of 53BP1 to DSBs. Because methylation of histone H3 Lys 79 was unaltered in response to DNA damage, we propose that 53BP1 senses DSBs indirectly through changes in higher-order chromatin structure that expose the 53BP1 binding site.

Suggested Citation

  • Yentram Huyen & Omar Zgheib & Richard A. DiTullio Jr & Vassilis G. Gorgoulis & Panayotis Zacharatos & Tom J. Petty & Emily A. Sheston & Hestia S. Mellert & Elena S. Stavridi & Thanos D. Halazonetis, 2004. "Methylated lysine 79 of histone H3 targets 53BP1 to DNA double-strand breaks," Nature, Nature, vol. 432(7015), pages 406-411, November.
    • Handle: RePEc:nat:nature:v:432:y:2004:i:7015:d:10.1038_nature03114
    DOI: 10.1038/nature03114
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    Cited by:

    1. Uta Eberlein & Michel Peper & Maria Fernández & Michael Lassmann & Harry Scherthan, 2015. "Calibration of the γ-H2AX DNA Double Strand Break Focus Assay for Internal Radiation Exposure of Blood Lymphocytes," PLOS ONE, Public Library of Science, vol. 10(4), pages 1-11, April.
    2. Xabier Vergara & Anna G. Manjón & Marcel Haas & Ben Morris & Ruben Schep & Christ Leemans & Anoek Friskes & Roderick L. Beijersbergen & Mathijs A. Sanders & René H. Medema & Bas Steensel, 2024. "Widespread chromatin context-dependencies of DNA double-strand break repair proteins," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    3. Aleix Bayona-Feliu & Emilia Herrera-Moyano & Nibal Badra-Fajardo & Iván Galván-Femenía & María Eugenia Soler-Oliva & Andrés Aguilera, 2023. "The chromatin network helps prevent cancer-associated mutagenesis at transcription-replication conflicts," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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