Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

ATM-mediated phosphorylation of the chromatin remodeling enzyme BRG1 modulates DNA double-strand break repair

Oncogene volume 34, pages 303–313 (2015)Cite this article

Subjects

Abstract

ATP-dependent chromatin remodeling complexes such as SWI/SNF (SWItch/Sucrose NonFermentable) have been implicated in DNA double-strand break (DSB) repair and damage responses. However, the regulatory mechanisms that control the function of chromatin remodelers in DNA damage response are largely unknown. Here, we show that ataxia telangiectasia mutated (ATM) mediates the phosphorylation of BRG1, the catalytic ATPase of the SWI/SNF complex that contributes to DSB repair by binding γ-H2AX-containing nucleosomes via interaction with acetylated histone H3 and stimulating γ-H2AX formation, at Ser-721 in response to DNA damage. ATM-mediated phosphorylation of BRG1 occurs rapidly and transiently after DNA damage. Phosphorylated BRG1 binds γ-H2AX-containing nucleosomes to form the repair foci. The Ser-721 phosphorylation of BRG1 is critical for binding γ-H2AX-containing nucleosomes and stimulating γ-H2AX formation and DSB repair. BRG1 binds to acetylated H3 peptides much better after phosphorylation at Ser-721 by DNA damage. However, the phosphorylation of Ser-721 does not significantly affect the ATPase and transcriptional activities of BRG1. These results, establishing BRG1 as a novel and functional ATM substrate, suggest that the ATM-mediated phosphorylation of BRG1 facilitates DSB repair by stimulating the association of this remodeler with γ-H2AX nucleosomes via enhancing the affinity to acetylated H3. Our work also suggests that the mechanism of BRG1 stimulation of DNA repair is independent of the remodeler’s enzymatic or transcriptional activities.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9

Similar content being viewed by others

References

  1. Jackson SP, Bartek J . The DNA-damage response in human biology and disease. Nature 2009; 461: 1071–1078.

    Article  CAS  Google Scholar 

  2. Ciccia A, Elledge SJ . The DNA damage response: making it safe to play with knives. Mol Cell 2010; 40: 179–204.

    Article  CAS  Google Scholar 

  3. van Attikum H, Gasser SM . Crosstalk between histone modifications during the DNA damage response. Trends Cell Biol 2009; 19: 207–217.

    Article  CAS  Google Scholar 

  4. Bonner WM, Redon CE, Dickey JS, Nakamura AJ, Sedelnikova OA, Solier S et al. GammaH2AX and cancer. Nat Rev Cancer. 2008; 8: 957–967.

    Article  CAS  Google Scholar 

  5. Lavin MF . Ataxia-telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer. Nat Rev Mol Cell Biol 2008; 9: 759–769.

    Article  CAS  Google Scholar 

  6. Kinner A, Wu W, Staudt C, Iliakis G . Gamma-H2AX in recognition and signaling of DNA double-strand breaks in the context of chromatin. Nucleic Acids Res 2008; 36: 5678–5694.

    Article  CAS  Google Scholar 

  7. Downs JA, Nussenzweig MC, Nussenzweig A . Chromatin dynamics and the preservation of genetic information. Nature 2007; 447: 951–958.

    Article  CAS  Google Scholar 

  8. Polo SE, Jackson SP . Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications. Genes Dev 2011; 25: 409–433.

    Article  CAS  Google Scholar 

  9. Lukas J, Lukas C, Bartek J . More than just a focus: the chromatin response to DNA damage and its role in genome integrity maintenance. Nat Cell Biol 2011; 13: 1161–1169.

    Article  CAS  Google Scholar 

  10. Sulli G, Di Micco R, d'Adda di Fagagna F . Crosstalk between chromatin state and DNA damage response in cellular senescence and cancer. Nat Rev Cancer 2012; 12: 709–720.

    Article  CAS  Google Scholar 

  11. Pandita TK, Richardson C . Chromatin remodeling finds its place in the DNA double-strand break response. Nucleic Acids Res 2009; 37: 1363–1377.

    Article  CAS  Google Scholar 

  12. Morrison AJ, Shen X . Chromatin remodelling beyond transcription: the INO80 and SWR1 complexes. Nat Rev Mol Cell Biol 2009; 10: 373–384.

    Article  CAS  Google Scholar 

  13. Conaway RC, Conaway JW . The INO80 chromatin remodeling complex in transcription, replication and repair. Trends Biochem Sci 2009; 34: 71–77.

    Article  CAS  Google Scholar 

  14. Downs JA, Allard S, Jobin-Robitaille O, Javaheri A, Auger A, Bouchard N et al. Binding of chromatin-modifying activities to phosphorylated histone H2A at DNA damage sites. Mol Cell 2004; 16: 979–990.

    Article  CAS  Google Scholar 

  15. Morrison AJ, Highland J, Krogan NJ, Arbel-Eden A, Greenblatt JF, Haber JE et al. INO80 and gamma-H2AX interaction links ATP-dependent chromatin remodeling to DNA damage repair. Cell 2004; 119: 767–775.

    Article  CAS  Google Scholar 

  16. van Attikum H, Fritsch O, Hohn B, Gasser SM . Recruitment of the INO80 complex by H2A phosphorylation links ATP-dependent chromatin remodeling with DNA double-strand break repair. Cell 2004; 119: 777–788.

    Article  CAS  Google Scholar 

  17. Tsukuda T, Fleming AB, Nickoloff JA, Osley MA . Chromatin remodelling at a DNA double-strand break site in Saccharomyces cerevisiae. Nature 2005; 438: 379–383.

    Article  CAS  Google Scholar 

  18. Morrison AJ, Kim JA, Person MD, Highland J, Xiao J, Wehr TS et al. Mec1/Tel1 phosphorylation of the INO80 chromatin remodeling complex influences DNA damage checkpoint responses. Cell 2007; 130: 499–511.

    Article  CAS  Google Scholar 

  19. Papamichos-Chronakis M, Krebs JE, Peterson CL . Interplay between Ino80 and Swr1 chromatin remodeling enzymes regulates cell cycle checkpoint adaptation in response to DNA damage. Genes Dev 2006; 20: 2437–2449.

    Article  CAS  Google Scholar 

  20. Falbo KB, Alabert C, Katou Y, Wu S, Han J, Wehr T et al. Involvement of a chromatin remodeling complex in damage tolerance during DNA replication. Nat Struct Mol Biol 2009; 16: 1167–1172.

    Article  CAS  Google Scholar 

  21. Papamichos-Chronakis M, Peterson CL . The Ino80 chromatin-remodeling enzyme regulates replisome function and stability. Nat Struct Mol Biol 2008; 15: 338–345.

    Article  CAS  Google Scholar 

  22. Shimada K, Oma Y, Schleker T, Kugou K, Ohta K, Harata M et al. Ino80 chromatin remodeling complex promotes recovery of stalled replication forks. Curr Biol 2008; 18: 566–575.

    Article  CAS  Google Scholar 

  23. Vincent JA, Kwong TJ, Tsukiyama T . ATP-dependent chromatin remodeling shapes the DNA replication landscape. Nat Struct Mol Biol 2008; 15: 477–484.

    Article  CAS  Google Scholar 

  24. Kato D, Waki M, Umezawa M, Aoki Y, Utsugi T, Ohtsu M et al. Phosphorylation of human INO80 is involved in DNA damage tolerance. Biochem Biophys Res Commun 2012; 417: 433–438.

    Article  CAS  Google Scholar 

  25. Chai B, Huang J, Cairns BR, Laurent BC . Distinct roles for the RSC and Swi/Snf ATP-dependent chromatin remodelers in DNA double-strand break repair. Genes Dev 2005; 19: 1656–1661.

    Article  CAS  Google Scholar 

  26. Shim EY, Ma JL, Oum JH, Yanez Y, Lee SE . The yeast chromatin remodeler RSC complex facilitates end joining repair of DNA double-strand breaks. Mol Cell Biol 2005; 25: 3934–3944.

    Article  CAS  Google Scholar 

  27. Shim EY, Hong SJ, Oum JH, Yanez Y, Zhang Y, Lee SE . RSC mobilizes nucleosomes to improve accessibility of repair machinery to the damaged chromatin. Mol Cell Biol 2007; 27: 1602–1613.

    Article  CAS  Google Scholar 

  28. Chambers AL, Brownlee PM, Durley SC, Beacham T, Kent NA, Downs JA . The two different isoforms of the RSC chromatin remodeling complex play distinct roles in DNA damage responses. PLoS One 2012; 7: e32016.

    Article  CAS  Google Scholar 

  29. Kent NA, Chambers AL, Downs JA . Dual chromatin remodeling roles for RSC during DNA double strand break induction and repair at the yeast MAT locus. J Biol Chem 2007; 282: 27693–27701.

    Article  CAS  Google Scholar 

  30. Liang B, Qiu J, Ratnakumar K, Laurent BC . RSC functions as an early double-strand-break sensor in the cell's response to DNA damage. Curr Biol 2007; 17: 1432–1437.

    Article  CAS  Google Scholar 

  31. Sinha M, Watanabe S, Johnson A, Moazed D, Peterson CL . Recombinational repair within heterochromatin requires ATP-dependent chromatin remodeling. Cell 2009; 138: 1109–1121.

    Article  CAS  Google Scholar 

  32. Wu S, Shi Y, Mulligan P, Gay F, Landry J, Liu H et al. A YY1-INO80 complex regulates genomic stability through homologous recombination-based repair. Nat Struct Mol Biol 2007; 14: 1165–1172.

    Article  CAS  Google Scholar 

  33. Park EJ, Hur SK, Kwon J . Human INO80 chromatin-remodelling complex contributes to DNA double-strand break repair via the expression of Rad54B and XRCC3 genes. Biochem J 2010; 431: 179–187.

    Article  CAS  Google Scholar 

  34. Gospodinov A, Vaissiere T, Krastev DB, Legube G, Anachkova B, Herceg Z . Mammalian ino80 mediates double strand break repair through its role in dna end strand resection. Mol Cell Biol 2011; 31: 4735–4745.

    Article  CAS  Google Scholar 

  35. Kashiwaba S, Kitahashi K, Watanabe T, Onoda F, Ohtsu M, Murakami Y . The mammalian INO80 complex is recruited to DNA damage sites in an ARP8 dependent manner. Biochem Biophys Res Commun 2010; 402: 619–625.

    Article  CAS  Google Scholar 

  36. Hur SK, Park EJ, Han JE, Kim YA, Kim JD, Kang D et al. Roles of human INO80 chromatin remodeling enzyme in DNA replication and chromosome segregation suppress genome instability. Cell Mol Life Sci 2010; 67: 2283–2296.

    Article  CAS  Google Scholar 

  37. Bao Y, Shen X . Chromatin remodeling in DNA double-strand break repair. Curr Opin Genet Dev 2007; 17: 126–131.

    Article  CAS  Google Scholar 

  38. Park JH, Park EJ, Lee HS, Kim SJ, Hur SK, Imbalzano AN et al. Mammalian SWI/SNF complexes facilitate DNA double-strand break repair by promoting gamma-H2AX induction. EMBO J 2006; 25: 3986–3997.

    Article  CAS  Google Scholar 

  39. Park JH, Park EJ, Hur SK, Kim S, Kwon J . Mammalian SWI/SNF chromatin remodeling complexes are required to prevent apoptosis after DNA damage. DNA Repair (Amst) 2009; 8: 29–39.

    Article  CAS  Google Scholar 

  40. Lee HS, Park JH, Kim SJ, Kwon SJ, Kwon J . A cooperative activation loop among SWI/SNF, gamma-H2AX and H3 acetylation for DNA double-strand break repair. EMBO J 2010; 29: 1434–1445.

    Article  CAS  Google Scholar 

  41. Matsuoka S, Ballif BA, Smogorzewska A, McDonald ER 3rd, Hurov KE, Luo J et al. ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science 2007; 316: 1160–1166.

    Article  CAS  Google Scholar 

  42. Bakkenist CJ, Kastan MB . DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 2003; 421: 499–506.

    Article  CAS  Google Scholar 

  43. Phelan ML, Sif S, Narlikar GJ, Kingston RE . Reconstitution of a core chromatin remodeling complex from SWI/SNF subunits. Mol Cell 1999; 3: 247–253.

    Article  CAS  Google Scholar 

  44. Hendricks KB, Shanahan F, Lees E . Role for BRG1 in cell cycle control and tumor suppression. Mol Cell Biol 2004; 24: 362–376.

    Article  CAS  Google Scholar 

  45. Oh J, Sohn DH, Ko M, Chung H, Jeon SH, Seong RH . BAF60a interacts with p53 to recruit the SWI/SNF complex. J Biol Chem 2008; 283: 11924–11934.

    Article  CAS  Google Scholar 

  46. Saha A, Wittmeyer J, Cairns BR . Chromatin remodelling: the industrial revolution of DNA around histones. Nat Rev Mol Cell Biol 2006; 7: 437–447.

    Article  CAS  Google Scholar 

  47. Ogiwara H, Ui A, Otsuka A, Satoh H, Yokomi I, Nakajima S et al. Histone acetylation by CBP and p300 at double-strand break sites facilitates SWI/SNF chromatin remodeling and the recruitment of non-homologous end joining factors. Oncogene 2011; 30: 2135–2146.

    Article  CAS  Google Scholar 

  48. Wilson BG, Roberts CW . SWI/SNF nucleosome remodellers and cancer. Nat Rev Cancer 2011; 11: 481–492.

    Article  CAS  Google Scholar 

  49. Bultman SJ, Herschkowitz JI, Godfrey V, Gebuhr TC, Yaniv M, Perou CM et al. Characterization of mammary tumors from Brg1 heterozygous mice. Oncogene 2008; 27: 460–468.

    Article  CAS  Google Scholar 

  50. Dykhuizen EC, Hargreaves DC, Miller EL, Cui K, Korshunov A, Kool M et al. BAF complexes facilitate decatenation of DNA by topoisomerase IIalpha. Nature 2013; 497: 624–627.

    Article  CAS  Google Scholar 

  51. Cohen SM, Chastain PD 2nd, Rosson GB, Groh BS, Weissman BE, Kaufman DG et al. BRG1 co-localizes with DNA replication factors and is required for efficient replication fork progression. Nucleic Acids Res 2010; 38: 6906–6919.

    Article  CAS  Google Scholar 

  52. Zhang L, Zhang Q, Jones K, Patel M, Gong F . The chromatin remodeling factor BRG1 stimulates nucleotide excision repair by facilitating recruitment of XPC to sites of DNA damage. Cell Cycle 2009; 8: 3953–3959.

    Article  CAS  Google Scholar 

  53. Zhao Q, Wang QE, Ray A, Wani G, Han C, Milum K et al. Modulation of nucleotide excision repair by mammalian SWI/SNF chromatin-remodeling complex. J Biol Chem 2009; 284: 30424–30432.

    Article  CAS  Google Scholar 

  54. Gong F, Fahy D, Liu H, Wang W, Smerdon MJ . Role of the mammalian SWI/SNF chromatin remodeling complex in the cellular response to UV damage. Cell Cycle 2008; 7: 1067–1074.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Rho H Seong (Seoul National University) for kindly providing the plasmids pREP4-p53RE-luc and flag-p53, and Seul-Ki Lee and Shin-Kyoung Hur for technical assistance. This work was supported by the National Research Foundation (NRF) grant funded by the Korea Ministry of Education and Science (MEST) (2012R1A2A2A01003744 to JK); the NRF grant funded by the MEST (2012R1A5A1048236); Ewha Global Top5 Grant 2013 and RP-Grant 2009 (to J-HP) funded by Ewha Womans University.

Author information

Author notes

  1. J-H Park

    Present address: 2Current Address: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Av. CLS 0624, Boston, MA 02115, USA.,

Authors and Affiliations

  1. Department of Life Science, College of Natural Sciences, The Research Center for Cellular Homeostasis, Ewha Womans University, Seoul, Republic of Korea

    S-J Kwon, J-H Park, E-J Park, S-A Lee, H-S Lee, S W Kang & J Kwon

Authors
  1. S-J Kwon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J-H Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E-J Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S-A Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. H-S Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S W Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J Kwon
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J Kwon.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kwon, SJ., Park, JH., Park, EJ. et al. ATM-mediated phosphorylation of the chromatin remodeling enzyme BRG1 modulates DNA double-strand break repair. Oncogene 34, 303–313 (2015). https://doi.org/10.1038/onc.2013.556

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2013.556

Keywords

This article is cited by

Search

Advanced search

Quick links