KAT5 tyrosine phosphorylation couples chromatin sensing to ATM signalling

  • This article was retracted on 11 April 2019

Abstract

The detection of DNA lesions within chromatin represents a critical step in cellular responses to DNA damage. However, the regulatory mechanisms that couple chromatin sensing to DNA-damage signalling in mammalian cells are not well understood. Here we show that tyrosine phosphorylation of the protein acetyltransferase KAT5 (also known as TIP60) increases after DNA damage in a manner that promotes KAT5 binding to the histone mark H3K9me3. This triggers KAT5-mediated acetylation of the ATM kinase, promoting DNA-damage-checkpoint activation and cell survival. We also establish that chromatin alterations can themselves enhance KAT5 tyrosine phosphorylation and ATM-dependent signalling, and identify the proto-oncogene c-Abl as a mediator of this modification. These findings define KAT5 tyrosine phosphorylation as a key event in the sensing of genomic and chromatin perturbations, and highlight a key role for c-Abl in such processes.

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Figure 1: KAT5 phosphorylation enhances its binding to H3K9me3.
Figure 2: KAT5 Tyr phosphorylation promotes ATM activation, checkpoint signalling and cell survival after ionizing radiation.
Figure 3: Chromatin alterations activate KAT5 phosphorylation and checkpoint signalling.
Figure 4: Chromatin binding promotes KAT5 phosphorylation.
Figure 5: c-Abl-dependent KAT5 tyrosine phosphorylation.

References

  1. 1

    Jackson, S. P. & Bartek, J. The DNA-damage response in human biology and disease. Nature 461, 1071–1078 (2009)

    ADS  CAS  Article  Google Scholar 

  2. 2

    Harper, J. W. & Elledge, S. J. The DNA damage response: ten years after. Mol. Cell 28, 739–745 (2007)

    CAS  Article  Google Scholar 

  3. 3

    Miller, K. M. & Jackson, S. P. Histone marks: repairing DNA breaks within the context of chromatin. Biochem. Soc. Trans. 40, 370–376 (2012)

    CAS  Article  Google Scholar 

  4. 4

    Downs, J. A., Nussenzweig, M. C. & Nussenzweig, A. Chromatin dynamics and the preservation of genetic information. Nature 447, 951–958 (2007)

    ADS  CAS  Article  Google Scholar 

  5. 5

    Bartek, J. & Lukas, J. DNA damage checkpoints: from initiation to recovery or adaptation. Curr. Opin. Cell Biol. 19, 238–245 (2007)

    CAS  Article  Google Scholar 

  6. 6

    Shiloh, Y. The ATM-mediated DNA-damage response: taking shape. Trends Biochem. Sci. 31, 402–410 (2006)

    CAS  Article  Google Scholar 

  7. 7

    Lee, J.-H. & Paull, T. T. Direct activation of the ATM protein kinase by the Mre11/Rad50/Nbs1 complex. Science 304, 93–96 (2004)

    ADS  CAS  Article  Google Scholar 

  8. 8

    Lee, J.-H. & Paull, T. T. ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex. Science 308, 551–554 (2005)

    ADS  CAS  Article  Google Scholar 

  9. 9

    Falck, J., Coates, J. & Jackson, S. P. Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage. Nature 434, 605–611 (2005)

    ADS  CAS  Article  Google Scholar 

  10. 10

    Uziel, T. et al. Requirement of the MRN complex for ATM activation by DNA damage. EMBO J. 22, 5612–5621 (2003)

    CAS  Article  Google Scholar 

  11. 11

    Ayoub, N., Jeyasekharan, A. D., Bernal, J. A. & Venkitaraman, A. R. HP1-beta mobilization promotes chromatin changes that initiate the DNA damage response. Nature 453, 682–686 (2008)

    ADS  CAS  Article  Google Scholar 

  12. 12

    Sun, Y. et al. Histone H3 methylation links DNA damage detection to activation of the tumour suppressor Tip60. Nature Cell Biol. 11, 1376–1382 (2009)

    CAS  Article  Google Scholar 

  13. 13

    Sun, Y., Xu, Y., Roy, K. & Price, B. D. DNA damage-induced acetylation of lysine 3016 of ATM activates ATM kinase activity. Mol. Cell. Biol. 27, 8502–8509 (2007)

    CAS  Article  Google Scholar 

  14. 14

    Kimura, A. & Horikoshi, M. Tip60 acetylates six lysines of a specific class in core histones in vitro. Genes Cells 3, 789–800 (1998)

    CAS  Article  Google Scholar 

  15. 15

    Sun, Y., Jiang, X., Chen, S., Fernandes, N. & Price, B. D. A role for the Tip60 histone acetyltransferase in the acetylation and activation of ATM. Proc. Natl Acad. Sci. USA 102, 13182–13187 (2005)

    ADS  CAS  Article  Google Scholar 

  16. 16

    Ziv, Y. et al. Chromatin relaxation in response to DNA double-strand breaks is modulated by a novel ATM- and KAP-1 dependent pathway. Nature Cell Biol. 8, 870–876 (2006)

    CAS  Article  Google Scholar 

  17. 17

    Kruhlak, M. J. et al. Changes in chromatin structure and mobility in living cells at sites of DNA double-strand breaks. J. Cell Biol. 172, 823–834 (2006)

    CAS  Article  Google Scholar 

  18. 18

    Bakkenist, C. J. & Kastan, M. B. DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421, 499–506 (2003)

    ADS  CAS  Article  Google Scholar 

  19. 19

    Hickson, I. et al. Identification and characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM. Cancer Res. 64, 9152–9159 (2004)

    CAS  Article  Google Scholar 

  20. 20

    Shafman, T. et al. Interaction between ATM protein and c-Abl in response to DNA damage. Nature 387, 520–523 (1997)

    CAS  Article  Google Scholar 

  21. 21

    Meltser, V., Ben-Yehoyada, M. & Shaul, Y. c-Abl tyrosine kinase in the DNA damage response: cell death and more. Cell Death Differ. 18, 2–4 (2011)

    CAS  Article  Google Scholar 

  22. 22

    Wang, X. et al. A positive role for c-Abl in Atm and Atr activation in DNA damage response. Cell Death Differ. 18, 5–15 (2011)

    Article  Google Scholar 

  23. 23

    Kharbanda, S. et al. Activation of the c-Abl tyrosine kinase in the stress response to DNA-damaging agents. Nature 376, 785–788 (1995)

    ADS  CAS  Article  Google Scholar 

  24. 24

    Baskaran, R. et al. Ataxia telangiectasia mutant protein activates c-Abl tyrosine kinase in response to ionizing radiation. Nature 387, 516–519 (1997)

    CAS  Article  Google Scholar 

  25. 25

    Buchdunger, E. et al. Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. Cancer Res. 56, 100–104 (1996)

    CAS  PubMed  Google Scholar 

  26. 26

    Mikkelsen, T. S. et al. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448, 553–560 (2007)

    ADS  CAS  Article  Google Scholar 

  27. 27

    Edmunds, J. W., Mahadevan, L. C. & Clayton, A. L. Dynamic histone H3 methylation during gene induction: HYPB/Setd2 mediates all H3K36 trimethylation. EMBO J. 27, 406–420 (2008)

    CAS  Article  Google Scholar 

  28. 28

    Chantalat, S. et al. Histone H3 trimethylation at lysine 36 is associated with constitutive and facultative heterochromatin. Genome Res. 21, 1426–1437 (2011)

    CAS  Article  Google Scholar 

  29. 29

    Jiang, Z. et al. Tip60-mediated acetylation activates transcription independent apoptotic activity of Abl. Mol. Cancer 10, 88 (2011)

    CAS  Article  Google Scholar 

  30. 30

    Brasher, B. B. & Van Etten, R. A. c-Abl has high intrinsic tyrosine kinase activity that is stimulated by mutation of the Src homology 3 domain and by autophosphorylation at two distinct regulatory tyrosines. J. Biol. Chem. 275, 35631–35637 (2000)

    CAS  Article  Google Scholar 

  31. 31

    Scaffidi, P. & Misteli, T. Lamin A-dependent nuclear defects in human aging. Science 312, 1059–1063 (2006)

    ADS  CAS  Article  Google Scholar 

  32. 32

    Pegoraro, G. & Misteli, T. The central role of chromatin maintenance in aging. Aging (Albany NY) 1, 1017–1022 (2009)

    CAS  Article  Google Scholar 

  33. 33

    Pegoraro, G. et al. Ageing-related chromatin defects through loss of the NURD complex. Nature Cell Biol. 11, 1261–1267 (2009)

    CAS  Article  Google Scholar 

  34. 34

    Lane, A. A. & Chabner, B. A. Histone deacetylase inhibitors in cancer therapy. J. Clin. Oncol. 27, 5459–5468 (2009)

    CAS  Article  Google Scholar 

  35. 35

    Podtcheko, A. et al. Inhibition of ABL tyrosine kinase potentiates radiation-induced terminal growth arrest in anaplastic thyroid cancer cells. Radiat. Res. 165, 35–42 (2006)

    ADS  CAS  Article  Google Scholar 

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Acknowledgements

We thank all members of the Jackson laboratory for help and support, and A. Blackford, S. Britton, K. Dry, J. Forment and J. Travers for critical reading of the manuscript. Research in the Jackson laboratory is funded by Cancer Research UK program grant C6/A11224, the European Research Council and the European Community Seventh Framework Programme grant agreement no. HEALTH-F2-2010-259893 (DDR). Core funding is provided by CRUK (C6946/A14492) and the Wellcome Trust (WT092096). S.P.J. receives his salary from the University of Cambridge, UK, supplemented by CRUK. A.K. is funded by a Herchel Smith Fellowship from the University of Cambridge.

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All experiments were conceived by A.K. and S.P.J. and were carried out by A.K. S.P.J. and A.K. wrote the paper.

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Correspondence to Stephen P. Jackson.

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The authors declare no competing financial interests.

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Kaidi, A., Jackson, S. KAT5 tyrosine phosphorylation couples chromatin sensing to ATM signalling. Nature 498, 70–74 (2013). https://doi.org/10.1038/nature12201

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