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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BackgroundMethodSelf-citation
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The 53BP1 Homolog in C. elegans Influences DNA Repair and Promotes Apoptosis in Response to Ionizing Radiation
Ryu, J. S., Kang, S., & Koo, H. (2013) · PLoS ONE · doi:10.1371/journal.pone.0064028 · Cited by 18
“The regions controlling nuclear focus formation (Foci) and the Tudor domains are also conserved [22,34].”
Background
A cell cycle-independent mode of the Rad9-Dpb11 interaction is induced by DNA damage
di Cicco, G., Bantele, S. C. S., Reußwig, K.-U., & Pfander, B. (2017) · Scientific Reports · doi:10.1038/s41598-017-11937-z · Cited by 18
UV sensitive mutations in histone H3 in Saccharomyces cerevisiae that alter specific K79 methylation states genetically act through distinct DNA repair pathways
Evans, M. L., Bostelman, L. J., Albrecht, A. M., Keller, A. M., Strande, N. T., & Thompson, J. S. (2008) · Current Genetics · doi:10.1007/s00294-008-0182-1 · Cited by 18
“K79 methylation is not altered in response to double stranded breaks, but it has been suggested that changes in chromatin structure caused by breaks might expose constitutive K79 methylation, enabling Rad9/53BP1 to bind to chromatin in order to initiate damage responses ( Huyen et al. 2004 ).”
BackgroundInfluential
Tudor hooks up with DNA repair
Corsini, L., & Sattler, M. (2007) · Nature Structural & Molecular Biology · doi:10.1038/nsmb0207-98 · Cited by 18
Chromatin organization modulates the origin of heritable structural variations in human genome
Roychowdhury, T., & Abyzov, A. S. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz103 · Cited by 16
“Thus, we concluded that NAHR around spontaneous DSBs likely arise as errors of HDR. Association of NAHR breakpoints with H3K79me2 (Supplementary Figure S7), might point toward regional bias for 53BP1 promoted error-free HDR.”
BackgroundInfluential
Systematic analysis of histone modification readout
Nikolov, M., & Fischle, W. (2012) · Molecular BioSystems · doi:10.1039/c2mb25328c · Cited by 17
PARP1 is required for preserving telomeric integrity but is dispensable for A-NHEJ
Harvey, A., Mielke, N., Grimstead, J. W., Jones, R. E., Nguyen, T., Mueller, M. R., Baird, D. M., & Hendrickson, E. A. (2018) · Oncotarget · doi:10.18632/oncotarget.26201 · Cited by 18
“We performed this assay in the various cell lines for both telomeric DNA and 53BP1, a common marker of DNA DSBs [59, 60].”
Method
CellTool: An Open-Source Software Combining Bio-Image Analysis and Mathematical Modeling for the Study of DNA Repair Dynamics
Danovski, G., Dyankova-Danovska, T., Stamatov, R., Aleksandrov, R., Kanev, P.-B., & Stoynov, S. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242316784 · Cited by 18
Trimethylation of histone H3K76 by Dot1B enhances cell cycle progression after mitosis in Trypanosoma cruzi
Nunes, V. S., Moretti, N. S., da Silva, M. S., Elias, M. C., Janzen, C. J., & Schenkman, S. (2020) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2020.118694 · Cited by 16
In vitro Assessment of the DNA Damage Response in Dental Mesenchymal Stromal Cells Following Low Dose X-ray Exposure
Belmans, N., Gilles, L., Welkenhuysen, J., Vermeesen, R., Baselet, B., Salmon, B. J. R., Baatout, S., Jacobs, R., Lucas, S., Lambrichts, I., et al. (2021) · Frontiers in Public Health · doi:10.3389/fpubh.2021.584484 · Cited by 16
“53BP1 is a known DNA DSB sensor and a mediator and effector in the DDR to DSBs (24, 30, 31).”
Background
Chromatin Ubiquitination Guides DNA Double Strand Break Signaling and Repair
Kolobynina, K. G., Rapp, A. W., & Cardoso, M. C. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.928113 · Cited by 17
Genome maintenance in the context of 4D chromatin condensation
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“Essentially, repair mechanisms loosen the nucleosome for accessibility of histones and repair factors [124, 125].”
DOT-1.1-dependent H3K79 methylation promotes normal meiotic progression and meiotic checkpoint function in C. elegans
Láscarez-Lagunas, L. I., Herruzo, E., Grishok, A., San-Segundo, P. A., & Colaiácovo, M. P. (2020) · PLoS Genetics · doi:10.1371/journal.pgen.1009171 · Cited by 16
“, H3K79me, H4K20me) supporting the recruitment of DNA damage checkpoint adaptors to activate the checkpoint [72,73].”
Background
Histone H3 K79 methylation states play distinct roles in UV-induced sister chromatid exchange and cell cycle checkpoint arrest in Saccharomyces cerevisiae
Rossodivita, A. A., Boudoures, A. L., Mecoli, J. P., Steenkiste, E. M., Karl, A. L., Vines, E. M., Cole, A. M., Ansbro, M. R., & Thompson, J. S. (2014) · Nucleic Acids Research · doi:10.1093/nar/gku242 · Cited by 18
“While some evidence has been published implicating this modification as a binding site for DNA repair factors (17), it is not yet clear if this modification is a docking site for repair machinery, a regulator of repair gene transcription, a modulator of repair-specific chromatin structures, or another function that ha…”
Background
Dpb4 promotes resection of DNA double-strand breaks and checkpoint activation by acting in two different protein complexes
Casari, E., Gobbini, E., Gnugnoli, M., Mangiagalli, M., Clerici, M., & Longhese, M. P. (2021) · Nature Communications · doi:10.1038/s41467-021-25090-9 · Cited by 19
Nbs1 moving up in the world
Stavridi, E. S., & Halazonetis, T. D. (2005) · Nature Cell Biology · doi:10.1038/ncb0705-648 · Cited by 16
Self-citation
Histone H2B Ubiquitylation and Deubiquitylation in Genomic RegulationPreprint
Emre, N. C. T., & Berger, S. L. (2004) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2004.69.289 · Cited by 16
Histone methylation can either promote or reduce cellular radiosensitivity by regulating DNA repair pathways
Zhou, Y., & Shao, C. (2020) · Mutation Research/Reviews in Mutation Research · doi:10.1016/j.mrrev.2020.108362 · Cited by 14
An emerging maestro of immune regulation: how DOT1L orchestrates the harmonies of the immune system
Kealy, L. C., Runting, J., Thiele, D., & Scheer, S. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1385319 · Cited by 15
“53BP1, a crucial component of double-strand DNA damage repair, requires DOT1L mediated H3K79 methylation for recruitment to damaged DNA (72).”
BackgroundInfluential
Metabolic perturbation of epigenome by inhibiting S -adenosylhomocysteine hydrolase elicits senescence through DNA damage response in hepatoma cells
Wu, G., Wang, N., Luo, Y., Zhang, Y., Wang, P., Zhu, Z., Gao, Y., Zhi, D., & Yang, B. (2017) · Tumor Biology · doi:10.1177/1010428317699117 · Cited by 17
Chromatin states responsible for the regulation of differentially expressed genes under 60Co~γ ray radiation in rice
Pan, X., Fang, Y., Xue-ming, Y., Zheng, D., Chen, L., Wang, L., Xiao, J., Wang, X., Wang, K., Cheng, Z., et al. (2017) · BMC Genomics · doi:10.1186/s12864-017-4172-x · Cited by 14
“The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. acetylation at H3K9 and H3K56 [12] and methylation at H3K79 [13] and H4K20 [14].”
BackgroundInfluential
Boundaries and physical characterization of a new domain shared between mammalian 53BP1 and yeast Rad9 checkpoint proteins
Alpha‐Bazin, B., Lorphelin, A., Nozerand, N., Charier, G., Marchetti, C., Bérenguer, F., Couprie, J., Gilquin, B., Zinn‐Justin, S., & Quéméneur, É. (2005) · Protein Science · doi:10.1110/ps.041305205 · Cited by 15
“Previously described as displaying chromatin-binding activity in vivo, the m53BP1 tandem-Tudor domain was found to bind methylated histone H3 (Huyen et al. 2004).”
BackgroundInfluential
Germline alterations in the 53BP1 gene in breast and ovarian cancer families
Rapakko, K., Heikkinen, K., Karppinen, S., Erkko, H., & Winqvist, R. (2006) · Cancer Letters · doi:10.1016/j.canlet.2006.01.021 · Cited by 15
Computational strategies to address chromatin structure problems
Perišić, O., & Tamar Schlick, A. (2016) · Physical Biology · doi:10.1088/1478-3975/13/3/035006 · Cited by 15
Tudor Domains as Methyl-Lysine and Methyl-Arginine Readers
Botuyan, M. V., & Mer, G. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-802389-1.00008-3 · Cited by 18
Histone Acetylation And Methylation
An, W. (2007) · Springer eBooks · doi:10.1007/1-4020-5466-1_16 · Cited by 15
“DOT1-mediated methylation of H3-K79 has also been identified as an interaction signal for tandem tudor domain of DSB check point protein 53BP1, and this interaction mediates the 53BP1 targeting to sites of DNA DSBs ( Huyen et al., 2004 ).”
Background
Dissection of Rad9 BRCT domain function in the mitotic checkpoint response to telomere uncapping
Nnakwe, C. C., Altaf, M., Côté, J., & Kron, S. J. (2009) · DNA repair · doi:10.1016/j.dnarep.2009.09.010 · Cited by 15
Epigenetic drug library screening reveals targeting DOT1L abrogates NAD+ synthesis by reprogramming H3K79 methylation in uveal melanoma
Gu, X., Hua, Y., Yu, J., Yang, L., Ge, S., Jia, R., Chai, P., Zhuang, A., & Fan, X. (2022) · Journal of Pharmaceutical Analysis · doi:10.1016/j.jpha.2022.11.008 · Cited by 13
Garlic‐derived compounds: Epigenetic modulators and their antitumor effects
Zhang, H., Wang, H., Qin, L., & Lin, S. (2024) · Phytotherapy Research · doi:10.1002/ptr.8108 · Cited by 14
“Histone methylation also showed an important role in the establishment of checklist control in the process of DNA damage repair (Huyen et al., 2004).”
Background
Multi-layered chromatin proteomics identifies cell vulnerabilities in DNA repair
Sigismondo, G., Arseni, L., Palacio‐Escat, N., Hofmann, T. G., Seiffert, M., & Krijgsveld, J. (2022) · Nucleic Acids Research · doi:10.1093/nar/gkac1264 · Cited by 14
“For instance, H3K79 acts as one of the docking sites for 53BP1 recruitment (79); however, its methylation level has been reported to be unchanged or to decrease upon DSB (16,92).”
Background
Ionizing radiation-induced foci persistence screen to discover enhancers of accelerated senescence
Kron, S. J., Labay, Efimova, I. V., Quarshie, Golden, & Weichselbaum (2011) · International Journal of High Throughput Screening · doi:10.2147/ijhts.s17076 · Cited by 14
Enhanced Protein Detection Using a Trapping Mode on a Hybrid Quadrupole Linear Ion Trap (Q-Trap)
Drogaris, P., Blanc, J. C. Y. L., Fitzgerald, J., Lowndes, N. F., Verreault, A., & Thibault, P. (2009) · Analytical Chemistry · doi:10.1021/ac9004259 · Cited by 14
TP53 and its Regulatory Genes as Prognosis of Cutaneous Melanoma
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GSE1 links the HDAC1/CoREST co-repressor complex to DNA damage
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“monoubiquitination levels in response to DNA -damage (6-10).”
Background
SMYD3 promotes endometrial cancer through epigenetic regulation of LIG4/XRCC4/XLF complex in non-homologous end joining repair
Huang, Y., Tang, M., Hu, Z., Cai, B., Chen, G., Jiang, L., Xia, Y., Guan, P., Li, X., Mao, Z., et al. (2024) · Oncogenesis · doi:10.1038/s41389-023-00503-0 · Cited by 15
DOT1L Mediates Stem Cell Maintenance and Represents a Therapeutic Vulnerability in Cancer
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“DOT1L-mediated H3K79me2 recruits the 53BP1 protein in humans (81) and its ortholog Rad9 in yeast (53) to DNA DSBs, thus linking this mark with DNA repair.”
Chromatin physics: Replacing multiple, representation-centered descriptions at discrete scales by a continuous, function-dependent self-scaled model
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Opportunities for translation: Targeting DNA repair pathways in pancreatic cancer
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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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