Cited by 884DNA Repair MechanismsGenomics and Chromatin DynamicsEpigenetics and DNA Methylation

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

Huyen, Yentram, Zgheib, Omar, DiTullio Jr, Richard A., Gorgoulis, Vassilis G., Zacharatos, Panayotis, Petty, Tom J., Sheston, Emily A., Mellert, Hestia S. +2 more·2004·Nature

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 sensor. 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.

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Crossref · 10.1038/nature03114

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  • Dual inhibitors of LSD1 and HDACs provide more effective and sustained inhibition of the REST corepressor 1 (CoREST) complex than existing class I HDAC inhibitors.

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Authors
Huyen, Y., Zgheib, O., DiTullio Jr, R. A., Gorgoulis, V. G., Zacharatos, P., Petty, T. J., Sheston, E. A., Mellert, H. S., Stavridi, E. S., & Halazonetis, T. D.
Affiliations
The Wistar Institute (US)
Corresponding author
Halazonetis, Thanos D.
Venue
Nature
Published
2004-11
Volume
432
Issue
7015
Pages
406-411
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
OpenAlex
W2038451572
Cited by
884
References
30
Citations by year
2026: 5 · 2025: 13 · 2024: 14 · 2023: 20 · 2022: 20 · 2021: 34 · 2020: 27 · 2019: 37 · 2018: 32 · 2017: 27 · 2016: 37 · 2015: 44 · 2014: 34 · 2013: 51 · 2012: 57
FWCI
22.90
Type
journal article
Language
en
Open access
closed
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • University of Pennsylvania
  • National Cancer Institute
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Keywords
53BP1, histone H3 lysine 79 methylation, DNA double-strand breaks, DNA damage checkpoint, Tudor domain, DOT1L, chromatin structure, DNA damage recognition, Rad9, protein-DNA interactions
MeSH terms
Tumor Suppressor p53-Binding Protein 1, Amino Acid Sequence, Binding Sites, Chromatin, Cross-Linking Reagents, DNA, DNA Damage, Histones, Humans, Lysine, Methylation, Methyltransferases, Models, Molecular, Molecular Sequence Data, Phosphoproteins, Protein Binding, Histone-Lysine N-Methyltransferase, Conserved Sequence, Protein Structure, Tertiary, Cell Line, Tumor, Intracellular Signaling Peptides and Proteins

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