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西亚试剂：Tip60 is a haplo-insufficient tumour suppressor required fo

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

Chiara Gorrini1,8, Massimo Squatrito1,8,9, Chiara Luise2, Nelofer Syed3, Daniele Perna1, Landon Wark4, Francesca Martinato1, Domenico Sardella1, Alessandro Verrecchia1, Samantha Bennett1, Stefano Confalonieri2, Matteo Cesaroni1, Francesco Marchesi5, Milena Gasco6, Eugenio Scanziani5, Maria Capra2, Sabine Mai4, Paolo Nuciforo2, Tim Crook3, John Lough7 & Bruno Amati1

  1. Department of Experimental Oncology, European Institute of Oncology (IEO),
  2. FIRC Institute of Molecular Oncology (IFOM), IFOM-IEO Campus, Milan 20139, Italy
  3. Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, Chester Beatty Laboratories, London, SW3 6JB, UK
  4. Manitoba Institute of Cell Biology and The Genomic Center for Cancer, Research and Diagnosis, CancerCare Manitoba, University of Manitoba, Winnipeg, Manitoba R3E 0V9, Canada
  5. Department of Veterinary Pathology, Hygiene and Public Health, Section of Veterinary and Avian Pathology, University of Milan, Milan 20133, Italy
  6. Department of Medical Oncology, San Croce e Carle Hospital, Cuneo 12100, Italy
  7. Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA
  8. These authors contributed equally to this work.
  9. Present address: Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.

Correspondence to: Bruno Amati1 Correspondence and requests for materials should be addressed to B.A. (Email: bruno.amati@ifom-ieo-campus.it).

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 Emu–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.