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Methylated lysine 79 of histone H3 targets 53BP1 to DNA double-strand breaks
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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“dual inhibitors of LSD1 and HDACs, which provide more effective and sustained inhibition of the REST corepressor 1 (CoREST) complex than existing class I HDAC inhibitors”
From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [207]
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“bound by 53BP1 (51), and in this case, the interaction”
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Cao, L., Xu, X., Bunting, S. F., Liu, J., Wang, R.-H., Cao, L. L., Wu, J. J., Peng, T.-N., Chen, J., Nussenzweig, A., et al. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.06.037 · Cited by 324
“Previous results have documented that 53BP1 recruitment to DNA requires specific alterations in histone lysine methylation (Botuyan et al., 2006; Huyen et al., 2004).”
BackgroundThe role of nuclear architecture in genomic instability and ageing.
Oberdoerffer, P., & Sinclair, D. A. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2238 · Cited by 305
“Recruitment of these factors is thought to tether the DNA-repair complex to the site of damag”
Background53BP1 facilitates long-range DNA end-joining during V(D)J recombination
Difilippantonio, S., Gapud, E. J., Wong, N., Huang, C., Mahowald, G. K., Chen, H. T., Kruhlak, M. J., Callén, E., Livák, F., Nussenzweig, M. C., et al. (2008) · Nature · doi:10.1038/nature07476 · Cited by 302
The histone code at DNA breaks: a guide to repair?
van Attikum, H., & Gasser, S. M. (2005) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1737 · Cited by 312
“The model discussed above arises in part from a study in mammalian cells by Huyen et al”
BackgroundMethylation of histone H3 lysine 36 enhances DNA repair by nonhomologous end-joining
Fnu, S., Williamson, E. A., Haro, L. P. D., Brenneman, M. A., Wray, J. W., Shaheen, M. F., Radhakrishnan, K., Lee, S., Nickoloff, J. A., & Hromas, R. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1013571108 · Cited by 300
Clouaire, T., Rocher, V., Lashgari, A., Arnould, C., Aguirrebengoa, M., Biernacka, A., Skrzypczak, M., Aymard, F., Fongang, B., Dojer, N., et al. (2018) · Molecular Cell · doi:10.1016/j.molcel.2018.08.020 · Cited by 314
“Conversely, we observed a clear loss of H3K79me2 and H2BK120ub, two histone modifications that were found, respectively, unchanged and increased at sites of breaks (Huyen et al., 2004; Moyal et al., 2011; Nakamura et al., 2011).”
CRISPR-mediated live imaging of genome editing and transcription
Wang, H., Nakamura, M., Abbott, T. R., Zhao, D., Luo, K., Yu, C., Nguyen, C. M., Lo, A., Daley, T., Russa, M. F. L., et al. (2019) · Science · doi:10.1126/science.aax7852 · Cited by 293
“We created a U2OS cell line that stably expressed a truncated 53BP1 protein (amino acid 1220-1711) fused with a fluorescent Apple protein, a well-characterized DNA DSB sensor ( 15 , 16 ).”
Tamburini, B. A. J., & Tyler, J. K. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.12.4903-4913.2005 · Cited by 299
“Methylated and ubiquitinated histones also appear to play an important role in the signaling of double-strand DNA damage to the cell (11, 15 , 40).”
BackgroundHuman USP3 Is a Chromatin Modifier Required for S Phase Progression and Genome Stability
Nicassio, F., Corrado, N., Vissers, J. H. A., Areces, L. B., Bergink, S., Marteijn, J. A. F., Geverts, B., Houtsmuller, A. B., Vermeulen, W., Fiore, P. P. D., et al. (2007) · Current Biology · doi:10.1016/j.cub.2007.10.034 · Cited by 301
“As shown in Figures 3C–3E, g-H2AX staining, as well as accumulation of the checkpoint protein 53BP1 [13] in nuclear foci, was enriched in USP3-KD U2OS cells.”
The emerging field of dynamic lysine methylation of non-histone proteins
Huang, J. L., & Berger, S. L. (2008) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2008.01.012 · Cited by 296
Wysocki, R., Javaheri, A., Allard, S., Sha, F., Côté, J., & Kron, S. J. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.19.8430-8443.2005 · Cited by 299
Chromatin dynamics and the preservation of genetic information
Downs, J. A., Nussenzweig, M. C., & Nussenzweig, A. (2007) · Nature · doi:10.1038/nature05980 · Cited by 296
“These remodelling events can make the lesion more accessible to 'damage sensor' proteins by exposing features of the nucleosome, such as constitutive histone modifications, that are normally concealed in the unperturbed cel”
BackgroundGiannattasio, M., Lazzaro, F., Plevani, P., & Muzi-Falconi, M. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m414453200 · Cited by 287
H2AX Prevents DNA Breaks from Progressing to Chromosome Breaks and Translocations
Franco, S., Gostissa, M., Zha, S., Lombard, D. B., Murphy, M. M., Zarrin, A. A., Yan, C., Tepsuporn, S., Morales, J. C., Adams, M. M., et al. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.01.005 · Cited by 282
“However, it also is conceivable that 53BP1 has additional roles in CSR, perhaps upstream of the DSB, via its ability to sensechromatin structural changes (Huyen et al., 2004).”
BackgroundInfluentialGenome-wide patterns of histone modifications in yeast
Millar, C. B., & Grunstein, M. R. (2006) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1986 · Cited by 298
Ezh2 Requires PHF1 To Efficiently Catalyze H3 Lysine 27 Trimethylation In Vivo
Sarma, K., Margueron, R., Ivanov, A. V., Pirrotta, V., & Reinberg, D. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.02017-07 · Cited by 303
“The TUDOR domain of 53BP1 was shown to bind histone H3K79me2 as well as H4K20me2 (2, 15).”
Focus on histone variant H2AX: To be or not to be
Yuan, J., Adamski, R., & Chen, J. (2010) · FEBS Letters · doi:10.1016/j.febslet.2010.05.021 · Cited by 301
“There are at least four ways that 53BP1 may be recruited and accumulate at DSB sites: (1) 53BP1 binds to methylated lysine 79 of histone H3 or dimethylated lysine 20 of histone H4 near or at DSBs [78,79]; (2) the GAR motif of 53BP1 is arginine methylated by PRMT1 and is necessary for 53BP1 DNA binding activity [111];…”
BackgroundBekker‐Jensen, S., Lukas, C., Melander, F., Bártek, J., & Lukas, J. (2005) · The Journal of Cell Biology · doi:10.1083/jcb.200503043 · Cited by 280
“Next, we exploited the recent discovery that the Tudor domain of 53BP1 directly interacts with H3-dmK79 ( Huyen et al., 2004 ), thereby determining the productive accumulation of 53BP1 in the IR-induced foci.”
BackgroundResultInfluentialThe functional diversity of protein lysine methylation
Lanouette, S., Mongeon, V., Figeys, D., & Couture, J. (2014) · Molecular Systems Biology · doi:10.1002/msb.134974 · Cited by 285
“For example, methylation of histones is associated with activity at transcription start sites (H3 K4 (SantosRosa et al, 2002)), heterochromatin formation (H3K9 (Bannister et al, 2001; Lachner et al, 2001)), X chromosome silencing and transcriptional repression (H3 K27 (Cao & Zhang, 2004; Plath, 2003)), transcriptional…”
BackgroundPhospho-Ser/Thr-binding domains: navigating the cell cycle and DNA damage response
Reinhardt, H. C., & Yaffe, M. B. (2013) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3640 · Cited by 269
Cellular senescence and Alzheimer disease: the egg and the chicken scenario
Saez-Atienzar, S., & Masliah, E. (2020) · Nature Reviews Neuroscience · doi:10.1038/s41583-020-0325-z · Cited by 257
Evolution of the Immunoglobulin Heavy Chain Class Switch Recombination Mechanism
Chaudhuri, J., Basu, U., Zarrin, A. A., Yan, C. T., Franco, S., Perlot, T., Vuong, B. Q., Wang, J. H., Phan, R. T., Datta, A., et al. (2007) · Advances in immunology · doi:10.1016/s0065-2776(06)94006-1 · Cited by 289
“For example, 53BP1 can be recruited to DSBs via its interaction with methylated lysine 79 of histone H3, a chromatin mark that may be exposed during chromatin remodeling following DNA damage (Huyen et al., 2004).”
BackgroundLee, H.-S., Park, J., Kim, S., Kwon, S.-J., & Kwon, J. (2010) · The EMBO Journal · doi:10.1038/emboj.2010.27 · Cited by 269
“…of the methylations at the Lys residues of H3 analysed, including K79 known to serve as the binding site of 53BP1 DNA damage checkpoint protein (Huyen et al, 2004), was affected by S139A mutation &2010 European Molecular Biology Organization The EMBO Journal VOL 29 | NO 8 | 2010 1435 (Figure…”
BackgroundTudor Domains Bind Symmetrical Dimethylated Arginines
Côté, J., & Richard, S. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m414328200 · Cited by 261
Stading, R. E., Gastelum, G. M., Chu, C., Jiang, W., & Moorthy, B. (2021) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2021.07.001 · Cited by 258
BMI1 Is Recruited to DNA Breaks and Contributes to DNA Damage-Induced H2A Ubiquitination and Repair
Ginjala, V., Nacerddine, K., Kulkarni, A., Oza, J., Hill, S. J., Yao, M., Citterio, E., van Lohuizen, M., & Ganesan, S. (2011) · Molecular and Cellular Biology · doi:10.1128/mcb.00981-10 · Cited by 240
“53BP1 recruitment to regions of DNA damage is dependent upon its Tudor domains, which have been found to specifically interact with methylated histone residues (6, 24, 42).”
BackgroundBRCA1 functions independently of homologous recombination in DNA interstrand crosslink repair
Bunting, S. F., Callén, E., Kozak, M. L., Kim, J. M., Wong, N., López-Contreras, A. J., Ludwig, T., Baer, R., Faryabi, R. B., Malhowski, A., et al. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.02.015 · Cited by 252
“Whereas Ku binds directly to exposed DNA ends, 53BP1 binds to a histone mark that is present in the entire chromatin area around the double-strand break (Botuyan et al., 2006; Huyen et al., 2004).”
BackgroundHistone methylation and the DNA damage response
Gong, F., & Miller, K. M. (2017) · Mutation Research/Reviews in Mutation Research · doi:10.1016/j.mrrev.2017.09.003 · Cited by 265
“In mammalian cells, although DOT1L-mediated H3K79me2 was reported to be important for 53BP1 binding in response to DSBs [41, 119], later studies have showed that the tandem tudor domain of 53BP1 preferentially binds to H4K20me2 at DSBs [37–39].”
BackgroundHistone H2B Ubiquitylation Controls Processive Methylation but Not Monomethylation by Dot1 and Set1
Shahbazian, M. D., Zhang, K., & Grunstein, M. R. (2005) · Molecular Cell · doi:10.1016/j.molcel.2005.06.010 · Cited by 249
Regulation of DNA End Joining, Resection, and Immunoglobulin Class Switch Recombination by 53BP1
Bothmer, A., Robbiani, D. F., Di Virgilio, M., Bunting, S. F., Klein, I. A., Feldhahn, N., Barlow, J., Chen, H.-T., Bosque, D., Callen, E., et al. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.03.019 · Cited by 244
“Human 53BP1 binds to the histone mark H4K20 via its tudor domain, and mutation of amino acid D1521 in the tudor domain abrogates 53BP1’s ability to form DNA damage foci in response to IR (Botuyan et al., 2006; Huyen et al., 2004).”
Influential
Metadata
- 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
- 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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