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


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.


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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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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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