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

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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., Stavridi, Elena S., Halazonetis, Thanos D.·2004·Nature

DOI 10.1038/nature03114

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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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Self-citation
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Items 401–500 of 883

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BackgroundInfluential
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Method
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Background
Interconnected contribution of tissue morphogenesis and the nuclear protein NuMA to the DNA damage response
Vidi, P., Chandramouly, G., Gray, M., Wang, L., Liu, E., Kim, J. J., Roukos, V., Bissell, M. J., Moghe, P. V., & Lelièvre, S. A. (2012) · Journal of Cell Science · doi:10.1242/jcs.089177 · Cited by 50
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Background
PTIP Regulates 53BP1 and SMC1 at the DNA Damage Sites
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Background
Histone modifications in DNA damage response
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Method
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Method
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“As 53BP1 specifically binds to a histone modification (37) and RPA binds to ssDNA (38) most probably unwound from nucleosomes, this might explain the nearby but not overlapping foci.”
Background
Inhibition of the Histone H3K27 Demethylase UTX Enhances Tumor Cell Radiosensitivity
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Background
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Background
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BackgroundInfluential
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Background
KDM4C (GASC1) lysine demethylase is associated with mitotic chromatin and regulates chromosome segregation during mitosis
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Background
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Background
Nutrients and Epigenetics
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Background
Structural Plasticity of Methyllysine Recognition by the Tandem Tudor Domain of 53BP1
Tong, Q., Cui, G., Botuyan, M. V., Rothbart, S. B., Hayashi, R., Musselman, C. A., Singh, N., Appella, E., Strahl, B. D., Mer, G., et al. (2015) · Structure · doi:10.1016/j.str.2014.11.013 · Cited by 39
“and weakly associates with some other dimethylated histones (Botuyan et al., 2006; Huyen et al., 2004; Kim et al., 2006), however a comprehensive analysis of the TTD substrates has not been performed.”
Influential
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Background
Histone modification and histone modification-targeted anti-cancer drugs in breast cancer: Fundamentals and beyond
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Background
Histone tails: Directing the chromatin response to DNA damage
Greenberg, R. A. (2011) · FEBS Letters · doi:10.1016/j.febslet.2011.05.037 · Cited by 36
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Background
Radiation biology and oncology in the genomic era
Kerns, S. L., Chuang, K., Hall, W. A., Werner, Z. A., Chen, Y., D, H. O. M., West, C., & Rosenstein, B. S. (2018) · British Journal of Radiology · doi:10.1259/bjr.20170949 · Cited by 37
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“Notably, Rad9, 53BP1, as well as the fission yeast orthologue Crb2 associate with chromatin and have all been shown to bind to nucleosomes, where they recognize specific histone modifications (Huyen et al., 2004; Nakamura et al., 2004; Sanders et al., 2004; Wysocki et al., 2005; Botuyan et al., 2006; Du et al., 2006;…”
Background
Competition effect in DNA damage response
Greubel, C., Hable, V., Drexler, G. A., Hauptner, A., Dietzel, S., Strickfaden, H., Baur, I., Krücken, R., Cremer, T. J., Dollinger, G., et al. (2008) · Radiation and Environmental Biophysics · doi:10.1007/s00411-008-0182-z · Cited by 37
“matin alterations [8, 9].”
Background
Rescue of gene-expression changes in an induced mouse model of spinal muscular atrophy by an antisense oligonucleotide that promotes inclusion of SMN2 exon 7
Staropoli, J. F., Huo, L., Chun, S. J., Allaire, N., Cullen, P. F., Thai, A., Fleet, C., Hua, Y., Bennett, C. F., Krainer, A. R., et al. (2015) · Genomics · doi:10.1016/j.ygeno.2015.01.007 · Cited by 36
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“Within a few minutes after introduction of a DSB, H3 becomes methylated at lysine 79 [66].”
Background
Time to Bloom
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“53BP1 accumulates at IRIF by interacting with methylated histones H3 and H4 via its Tudor domain [33, 34 ].”
Background
Induction of DNA Double-Strand Breaks and Cellular Migration Through Bystander Effects in Cells Irradiated With the Slit-Type Microplanar Beam of the Spring-8 Synchrotron
Kashino, G., Kondoh, T., Nariyama, N., Umetani, K., Ohigashi, T., Shinohara, K., Kurihara, A., Fukumoto, M., Tanaka, H., Maruhashi, A., et al. (2009) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/j.ijrobp.2008.09.060 · Cited by 35
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“…activity is involved in embryonic development and differentiation (Jones et al. 2008; Barry et al. 2009), cardiac function (Nguyen et al. 2011), hematopoiesis (Feng et al. 2010; Jo et al. 2011), cell proliferation and aging (Kim et al. 2012b) and chondrogenesis (Castaño Betancourt et al. 2012).”
Chromatin modifications and DNA double-strand breaks: the current state of play
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Protein Phosphatase 5 Regulates the Function of 53BP1 after Neocarzinostatin-induced DNA Damage
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Background
Targeting the epigenetics of the DNA damage response in breast cancer
Montenegro, M. F., González-Guerrero, R., Sánchez‐del‐Campo, L., Piñero, A., Cabezas‐Herrera, J., & Rodríguez‐López, J. N. (2016) · Cell Death and Disease · doi:10.1038/cddis.2016.85 · Cited by 34
A role of the 53BP1 protein in genome protection: structural and functional characteristics of 53BP1-dependent DNA repair
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“However, this epigenetic landscape enables the binding of the 53BP1 protein to damaged chromatin [107].”
Background
S1219 residue of 53BP1 is phosphorylated by ATM kinase upon DNA damage and required for proper execution of DNA damage response
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“Two other histone PTMs, dimethylated lysine 20 of histone H4 (in mammals) and methylated lysine 79 of histone H3, constitutively present in a large fraction of chromatin, help recruiting checkpoint mediators (Rad9 or its human and fission yeast orthologs 53BP1 and Crb2) at DSBs (Botuyan et al., 2006; Huyen et al., 200…”
Background
Chromatin and the DNA damage response
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The Fission Yeast Crb2/Chk1 Pathway Coordinates the DNA Damage and Spindle Checkpoint in Response to Replication Stress Induced by Topoisomerase I Inhibitor
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“The sequence similarity concerns the C-terminal BRCT domains, which are protein-protein interaction domains (5), and the two tandem Tudor folds in the central part of the proteins, which are protein-protein and protein-DNA interaction domains (8, 15 ).”
Background
Chromatin Modifications in DNA Repair
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“Researchers investigating the involvement of methylated lysine 79 in histone H3 decreased expression of Dot1 and found that there were reduced levels of 53BP1 immunofluorescent foci following ionizing radiation treatment (Huyen et al. 2004).”
Background
Transcription-coupled DNA double-strand break repair
Guha, S., & Bhaumik, S. R. (2021) · DNA repair · doi:10.1016/j.dnarep.2021.103211 · Cited by 34
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“In addition, the foci numbers of 53BP1, a sensor of DNA damage [26], were compared between 10 healthy controls and 47 RC patients.”
BackgroundInfluential
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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.
ORCID: Zgheib, Omar
Gorgoulis, Vassilis G.
Halazonetis, Thanos D.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2004-11
Volume: 432
Issue: 7015
Pages: 406-411
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature03114
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
Licence: www.springer.com/tdm (tdm)
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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Methylated lysine 79 of histone H3 targets 53BP1 to DNA double-strand breaks

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