DNA is packaged into chromatin, a highly compacted DNA–protein complex; therefore, all cellular processes that use the DNA as a template, including DNA repair, require a high degree of coordination between the DNA-repair machinery and chromatin modification/remodelling, which regulates the accessibility of DNA in chromatin. Recent studies have implicated histone acetyltransferase (HAT) complexes and chromatin acetylation in DNA repair; however, the precise underlying mechanism remains poorly understood1,2. Here, we show that the HAT cofactor Trrap and Tip60 HAT bind to the chromatin surrounding sites of DNA double-strand breaks (DSBs) in vivo. Trrap depletion impairs both DNA-damage-induced histone H4 hyperacetylation and accumulation of repair molecules at sites of DSBs, resulting in defective homologous recombination (HR) repair, albeit with the presence of a functional ATM-dependent DNA-damage signalling cascade. Importantly, the impaired loading of repair proteins and the defect in DNA repair in Trrap-deficient cells can be counteracted by chromatin relaxation, indicating that the DNA-repair defect that was observed in the absence of Trrap is due to impeded chromatin accessibility at sites of DNA breaks. Thus, these data reveal that cells may use the same basic mechanism involving HAT complexes to regulate distinct cellular processes, such as transcription and DNA repair.
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Carrozza, M. J., Utley, R. T., Workman, J. L. & Cote, J. The diverse functions of histone acetyltransferase complexes. Trends Genet. 19, 321–329 (2003).
Peterson, C. L. & Cote, J. Cellular machineries for chromosomal DNA repair. Genes Dev. 18, 602–616 (2004).
Kurdistani, S. K. & Grunstein, M. Histone acetylation and deacetylation in yeast. Nature Rev. Mol. Cell. Biol. 4, 276–284 (2003).
Bird, A. W. et al. Acetylation of histone H4 by Esa1 is required for DNA double-strand break repair. Nature 419, 411–415 (2002).
Qin, S. & Parthun, M. R. Histone H3 and the histone acetyltransferase Hat1p contribute to DNA double-strand break repair. Mol. Cell. Biol. 22, 8353–8365 (2002).
Kusch, T. et al. Acetylation by Tip60 is required for selective histone variant exchange at DNA lesions. Science 306, 2084–2087 (2004).
Ikura, T. et al. Involvement of the TIP60 histone acetylase complex in DNA repair and apoptosis. Cell 102, 463–473 (2000).
Martinez, E. et al. Human STAGA complex is a chromatin-acetylating transcription coactivator that interacts with pre-mRNA splicing and DNA damage-binding factors in vivo. Mol. Cell. Biol. 21, 6782–6795 (2001).
Tamburini, B. A. & Tyler, J. K. Localized histone acetylation and deacetylation triggered by the homologous recombination pathway of double-strand DNA repair. Mol. Cell. Biol. 25, 4903–4913 (2005).
Downs, J. A. et al. Binding of chromatin-modifying activities to phosphorylated histone H2A at DNA damage sites. Mol. Cell 16, 979–990 (2004).
Brand, M. et al. UV-damaged DNA-binding protein in the TFTC complex links DNA damage recognition to nucleosome acetylation. EMBO J. 20, 3187–3196 (2001).
Utley, R. T., Lacoste, N., Jobin-Robitaille, O., Allard, S. & Cote, J. Regulation of NuA4 histone acetyltransferase activity in transcription and DNA repair by phosphorylation of histone H4. Mol. Cell. Biol. 25, 8179–8190 (2005).
McMahon, S. B., Van Buskirk, H. A., Dugan, K. A., Copeland, T. D. & Cole, M. D. The novel ATM-related protein TRRAP is an essential cofactor for the c-Myc and E2F oncoproteins. Cell 94, 363–374 (1998).
Deleu, L., Shellard, S., Alevizopoulos, K., Amati, B. & Land, H. Recruitment of TRRAP required for oncogenic transformation by E1A. Oncogene 20, 8270–8275 (2001).
Frank, S. R., Schroeder, M., Fernandez, P., Taubert, S. & Amati, B. Binding of c-Myc to chromatin mediates mitogen-induced acetylation of histone H4 and gene activation. Genes Dev. 15, 2069–2082 (2001).
McMahon, S. B., Wood, M. A. & Cole, M. D. The essential cofactor TRRAP recruits the histone acetyltransferase hGCN5 to c-Myc. Mol. Cell. Biol. 20, 556–562 (2000).
Herceg, Z. et al. Disruption of Trrap causes early embryonic lethality and defects in cell cycle progression. Nature Genet. 29, 206–211 (2001).
Olive, P. L., Banath, J. P. & Durand, R. E. Heterogeneity in radiation-induced DNA damage and repair in tumor and normal cells measured using the “comet” assay. Radiat. Res. 122, 86–94 (1990).
Pierce, A. J., Hu, P., Han, M., Ellis, N. & Jasin, M. Ku DNA end-binding protein modulates homologous repair of double-strand breaks in mammalian cells. Genes Dev. 15, 3237–3242 (2001).
Schultz, L. B., Chehab, N. H., Malikzay, A. & Halazonetis, T. D. p53 binding protein 1 (53BP1) is an early participant in the cellular response to DNA double-strand breaks. J. Cell Biol. 151, 1381–1390 (2000).
Rappold, I., Iwabuchi, K., Date, T. & Chen, J. Tumor suppressor p53 binding protein 1 (53BP1) is involved in DNA damage-signaling pathways. J. Cell Biol. 153, 613–620 (2001).
Stucki, M. & Jackson, S. P. MDC1/NFBD1: a key regulator of the DNA damage response in higher eukaryotes. DNA Repair 3, 953–957 (2004).
Bekker-Jensen, S., Lukas, C., Melander, F., Bartek, J. & Lukas, J. Dynamic assembly and sustained retention of 53BP1 at the sites of DNA damage are controlled by Mdc1/NFBD1. J. Cell Biol. 170, 201–211 (2005).
Powell, S. N. & Kachnic, L. A. Roles of BRCA1 and BRCA2 in homologous recombination, DNA replication fidelity and the cellular response to ionizing radiation. Oncogene 22, 5784–5791 (2003).
Masson, J. Y. & West, S. C. The Rad51 and Dmc1 recombinases: a non-identical twin relationship. Trends Biochem. Sci. 26, 131–136 (2001).
Bakkenist, C. J. & Kastan, M. B. DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421, 499–506 (2003).
Falck, J., Mailand, N., Syljuasen, R. G., Bartek, J. & Lukas, J. The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis. Nature 410, 842–847 (2001).
Choy, J. S. & Kron, S. J. NuA4 subunit Yng2 function in intra-S-phase DNA damage response. Mol. Cell. Biol. 22, 8215–8225 (2002).
Brand, M., Yamamoto, K., Staub, A. & Tora, L. Identification of TATA-binding protein-free TAFII-containing complex subunits suggests a role in nucleosome acetylation and signal transduction. J. Biol. Chem. 274, 18285–18289 (1999).
Huyen, Y. et al. Methylated lysine 79 of histone H3 targets 53BP1 to DNA double-strand breaks. Nature 432, 406–411 (2004).
Cairns, B. R. Emerging roles for chromatin remodeling in cancer biology. Trends Cell Biol. 11, S15–S21 (2001).
Yang, X. J. The diverse superfamily of lysine acetyltransferases and their roles in leukemia and other diseases. Nucleic Acids Res. 32, 959–976 (2004).
Li, H., Cuenin, C., Murr, R., Wang, Z. Q. & Herceg, Z. HAT cofactor Trrap regulates the mitotic checkpoint by modulation of Mad1 and Mad2 expression. EMBO J. 23, 4824–4834 (2004).
Richardson, C., Moynahan, M. E. & Jasin, M. Double-strand break repair by interchromosomal recombination: suppression of chromosomal translocations. Genes Dev. 12, 3831–3842 (1998).
Herceg, Z. et al. Genome-wide analysis of gene expression regulated by the HAT cofactor Trrap in conditional knockout cells. Nucleic Acids Res. 31, 7011–7023 (2003).
We thank M. Jasin (Memorial Sloan-Kettering Cancer Center, New York, NY) for hprt–DRGFP and pCBASce vectors, D. Livingston (Harvard Medical School, Boston, MA) for anti-BRCA1 antibodies, J. Chen (Mayo Clinic, Rochester, MN) for anti-53BP1 and anti-Mdc1 antibodies, L. Tora (Institut de Genetique et de Biologie Moleculaire et Cellulaire, IGBMC, Illkirch, France) for anti-TRRAP antibodies and communicating unpublished results, and S. Kochbin (Institut Albert Bonniot, La Tronche, France) for Tip60 constructs. We also thank V. Shukla for help in cell culture and M.-P. Cros for the maintenance of mouse colonies and assistance in collecting blastocysts. Further thanks are due to J. Hall, B. Sylla and M. Finkbeiner for critical reading of the manuscript and helpful discussions. We are grateful to J. Cheney and M. Renaud for editing the manuscript. R.M. is supported by a PhD fellowship from la Ligue Nationale (Française) Contre le Cancer. J.I.L. is supported by a postdoctoral fellowship from the International Agency for Research on Cancer (IARC) and by an EMBO long-term fellowship. This work was supported by the Association pour la Recherche sur le Cancer (ARC), France and the Association for International Cancer Research (AICR), UK.
The authors declare no competing financial interests.
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