Tip60 is a haplo-insufficient tumour suppressor required for an oncogene-induced DNA damage response

Abstract

The acetyl-transferase Tip60 might influence tumorigenesis in multiple ways1. First, Tip60 is a co-regulator of transcription factors that either promote or suppress tumorigenesis, such as Myc and p532,3,4. Second, Tip60 modulates DNA-damage response (DDR) signalling1, and a DDR triggered by oncogenes can counteract tumour progression5,6. Using Eμ–myc transgenic mice that are heterozygous for a Tip60 gene (Htatip) knockout allele (hereafter denoted as Tip60+/– mice), we show that Tip60 counteracts Myc-induced lymphomagenesis in a haplo-insufficient manner and in a time window that is restricted to a pre- or early-tumoral stage. Tip60 heterozygosity severely impaired the Myc-induced DDR7,8,9 but caused no general DDR defect in B cells. Myc- and p53-dependent transcription were not affected, and neither were Myc-induced proliferation, activation of the ARF–p53 tumour suppressor pathway or the resulting apoptotic response10,11,12,13. We found that the human TIP60 gene (HTATIP) is a frequent target for mono-allelic loss in human lymphomas and head-and-neck and mammary carcinomas, with concomitant reduction in mRNA levels. Immunohistochemical analysis also demonstrated loss of nuclear TIP60 staining in mammary carcinomas. These events correlated with disease grade and frequently concurred with mutation of p53. Thus, in both mouse and human, Tip60 has a haplo-insufficient tumour suppressor activity that is independent from—but not contradictory with—its role within the ARF–p53 pathway1,2,3,14,15,16. We suggest that this is because critical levels of Tip60 are required for mounting an oncogene-induced DDR in incipient tumour cells5,6, the failure of which might synergize with p53 mutation towards tumour progression17,18,19,20.

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Figure 1: Tip60 haplo-insufficiency accelerates Myc-induced lymphomagenesis but does not alleviate the pressure for p53 inactivation.
Figure 2: Tip60 haplo-insufficiency does not affect B-cell homeostasis, but abrogates a Myc-induced DDR.
Figure 3: Tip60 haplo-insufficiency does not affect Myc- and p53-dependent transcription.
Figure 4: TIP60 is a haplo-insufficient tumour suppressor in human tumours.

References

  1. 1

    Squatrito, M., Gorrini, C. & Amati, B. Tip60 in DNA damage response and growth control: many tricks in one HAT. Trends Cell Biol. 16, 433–442 (2006)

  2. 2

    Tang, Y., Luo, J., Zhang, W. & Gu, W. Tip60-dependent acetylation of p53 modulates the decision between cell-cycle arrest and apoptosis. Mol. Cell 24, 827–839 (2006)

  3. 3

    Sykes, S. M. et al. Acetylation of the p53 DNA-binding domain regulates apoptosis induction. Mol. Cell 24, 841–851 (2006)

  4. 4

    Frank, S. R. et al. Myc recruits the Tip60 histone acetyl-transferase complex to chromatin. EMBO Rep. 4, 575–580 (2003)

  5. 5

    Bartkova, J. et al. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434, 864–870 (2005)

  6. 6

    Gorgoulis, V. G. et al. Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature 434, 907–913 (2005)

  7. 7

    Prochownik, E. V. & Li, Y. The ever expanding role for c-Myc in promoting genomic instability. Cell Cycle 6, 1024–1029 (2007)

  8. 8

    Pusapati, R. V. et al. ATM promotes apoptosis and suppresses tumorigenesis in response to Myc. Proc. Natl Acad. Sci. USA 103, 1446–1451 (2006)

  9. 9

    Reimann, M. et al. The Myc-evoked DNA damage response accounts for treatment resistance in primary lymphomas in vivo. Blood 11 June 2007 (doi: 10.1182/blood-2007-02-075614).

  10. 10

    Eischen, C. M., Weber, J. D., Roussel, M. F., Sherr, C. J. & Cleveland, J. L. Disruption of the ARF-Mdm2-p53 tumor suppressor pathway in Myc-induced lymphomagenesis. Genes Dev. 13, 2658–2669 (1999)

  11. 11

    Schmitt, C. A., McCurrach, M. E., de Stanchina, E., Wallace-Brodeur, R. R. & Lowe, S. W. INK4a/ARF mutations accelerate lymphomagenesis and promote chemoresistance by disabling p53. Genes Dev. 13, 2670–2677 (1999)

  12. 12

    Eischen, C. M., Roussel, M. F., Korsmeyer, S. J. & Cleveland, J. L. Bax loss impairs Myc-induced apoptosis and circumvents the selection of p53 mutations during Myc-mediated lymphomagenesis. Mol. Cell. Biol. 21, 7653–7662 (2001)

  13. 13

    Schmitt, C. A. et al. Dissecting p53 tumor suppressor functions in vivo. Cancer Cell 1, 289–298 (2002)

  14. 14

    Berns, K. et al. A large-scale RNAi screen in human cells identifies new components of the p53 pathway. Nature 428, 431–437 (2004)

  15. 15

    Tyteca, S., Vandromme, M., Legube, G., Chevillard-Briet, M. & Trouche, D. Tip60 and p400 are both required for UV-induced apoptosis but play antagonistic roles in cell cycle progression. EMBO J. 25, 1680–1689 (2006)

  16. 16

    Legube, G. et al. Role of the histone acetyl transferase Tip60 in the p53 pathway. J. Biol. Chem. 279, 44825–44833 (2004)

  17. 17

    Westphal, C. H. et al. atm and p53 cooperate in apoptosis and suppression of tumorigenesis, but not in resistance to acute radiation toxicity. Nature Genet. 16, 397–401 (1997)

  18. 18

    Celeste, A. et al. H2AX haploinsufficiency modifies genomic stability and tumor susceptibility. Cell 114, 371–383 (2003)

  19. 19

    Bassing, C. H. et al. Histone H2AX: a dosage-dependent suppressor of oncogenic translocations and tumors. Cell 114, 359–370 (2003)

  20. 20

    Morales, J. C. et al. 53BP1 and p53 synergize to suppress genomic instability and lymphomagenesis. Proc. Natl Acad. Sci. USA 103, 3310–3315 (2006)

  21. 21

    Nilsson, J. A. et al. Targeting ornithine decarboxylase in Myc-induced lymphomagenesis prevents tumor formation. Cancer Cell 7, 433–444 (2005)

  22. 22

    Sancar, A., Lindsey-Boltz, L. A., Unsal-Kacmaz, K. & Linn, S. Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu. Rev. Biochem. 73, 39–85 (2004)

  23. 23

    Eymin, B. et al. p14ARF activates a Tip60-dependent and p53-independent ATM/ATR/CHK pathway in response to genotoxic stress. Mol. Cell. Biol. 26, 4339–4350 (2006)

  24. 24

    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)

  25. 25

    Shreeram, S. et al. Regulation of ATM/p53-dependent suppression of myc-induced lymphomas by Wip1 phosphatase. J. Exp. Med. 203, 2793–2799 (2006)

  26. 26

    Jiang, X., Sun, Y., Chen, S., Roy, K. & Price, B. D. The FATC domains of PIKK proteins are functionally equivalent and participate in the Tip60-dependent activation of DNA-PKcs and ATM. J. Biol. Chem. 281, 15741–15746 (2006)

  27. 27

    Lehner, B., Crombie, C., Tischler, J., Fortunato, A. & Fraser, A. G. Systematic mapping of genetic interactions in Caenorhabditis elegans identifies common modifiers of diverse signaling pathways. Nature Genet. 38, 896–903 (2006)

  28. 28

    Dominguez-Sola, D. et al. Non-transcriptional control of DNA replication by c-Myc. Nature 448, 445–451 (2007)

  29. 29

    Sharpless, N. E. INK4a/ARF: a multifunctional tumor suppressor locus. Mutat. Res. 576, 22–38 (2005)

  30. 30

    Hemann, M. T. et al. Suppression of tumorigenesis by the p53 target PUMA. Proc. Natl Acad. Sci. USA 101, 9333–9338 (2004)

  31. 31

    Adams, J. M. et al. The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature 318, 533–538 (1985)

  32. 32

    Jacks, T. et al. Tumor spectrum analysis in p53-mutant mice. Curr. Biol. 4, 1–7 (1994)

  33. 33

    Kamijo, T. et al. Loss of the ARF tumor suppressor reverses premature replicative arrest but not radiation hypersensitivity arising from disabled atm function. Cancer Res. 59, 2464–2469 (1999)

  34. 34

    Corcoran, L. M., Cory, S. & Adams, J. M. Transposition of the immunoglobulin heavy chain enhancer to the myc oncogene in a murine plasmacytoma. Cell 40, 71–79 (1985)

  35. 35

    Rubinson, D. A. et al. A lentivirus-based system to functionally silence genes in primary mammalian cells, stem cells and transgenic mice by RNA interference. Nature Genet. 33, 401–406 (2003)

  36. 36

    Kamer, I. et al. Proapoptotic BID is an ATM effector in the DNA-damage response. Cell 122, 593–603 (2005)

  37. 37

    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)

  38. 38

    Eberwine, J. et al. Analysis of gene expression in single live neurons. Proc. Natl Acad. Sci. USA 89, 3010–3014 (1992)

  39. 39

    Benjamini, Y. & Hochberg, Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. Roy. Stat. Soc. B. 57, 289–300 (1995)

  40. 40

    Bergamaschi, D. et al. p53 polymorphism influences response in cancer chemotherapy via modulation of p73-dependent apoptosis. Cancer Cell 3, 387–402 (2003)

  41. 41

    Crighton, D. et al. DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell 126, 121–134 (2006)

  42. 42

    Syed, N. et al. Transcriptional silencing of Polo-like kinase 2 (SNK/PLK2) is a frequent event in B-cell malignancies. Blood 107, 250–256 (2006)

  43. 43

    Kononen, J. et al. Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nature Med. 4, 844–847 (1998)

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Acknowledgements

We thank S. Campaner, G. Natoli, G. Del Sal, M. Foiani, F. d’Adda di Fagagna, E. Belloni and H. Müller for discussions and comments, F. Contegno for laboratory set-up and management, A. Gobbi, M. Capillo and B. Giulini for management of mouse colonies, L. Tizzoni and L. Bernard for qPCR, I. Muradore for FACS analysis, J. Cleveland and J.-C. Marine for Eμ–myc and p53 knockout mice, A. Gross for phospho-Bid antibodies and P.-G. Pelicci for his continuous support. This work was supported by the Italian Association for Cancer Research (AIRC) and the ‘Ricerca Finalizzata’ program of the Italian Health Ministry (to B.A.), in part by the NIH (to J.L.) and by the National Cancer Institute of Canada and CancerCare Manitoba Foundation (to S.M.).

Author Contributions C.G., M.S. and B.A. conceived the work and designed the experiments. B.A. supervised the project and wrote the manuscript. C.G. and M.S. performed all of the experimental work on mice and cells, with the exceptions listed below. F. Martinato optimized the ChIP assays on freshly isolated B-cells. S.B. characterized Tip60+/– MEFs. D.P. performed the experiments in ARF and ATM knockout MEFs. D.S. performed the genotyping of all mice. S.C. and M. Cesaroni contributed bioinformatic analysis. L.W. and S.M. performed cytogenetic analysis of telomeres in B cells. F. Marchesi and E.S. performed the mouse pathology. A.V. constructed and optimized the Tip60 shRNA and provided technical assistance. N.S., M.G. and T.C. contributed the genetic analysis of human tumours. C.L., M. Capra and P.N. produced and analysed the IHC data on human tumours. J.L. constructed the Tip60+/– mice.

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Correspondence to Bruno Amati.

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This file contains Supplementary Tables 1-2 and Supplementary Figures 1-9 with Legends. (PDF 27465 kb)

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Gorrini, C., Squatrito, M., Luise, C. et al. Tip60 is a haplo-insufficient tumour suppressor required for an oncogene-induced DNA damage response. Nature 448, 1063–1067 (2007). https://doi.org/10.1038/nature06055

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