Oncogenesis by sequestration of CBP/p300 in transcriptionally inactive hyperacetylated chromatin domains |
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| Authors: | Nicolas Reynoird Brian E Schwartz Manuela Delvecchio Karin Sadoul David Meyers Chandrani Mukherjee C��cile Caron Hiroshi Kimura Sophie Rousseaux Philip A Cole Daniel Panne Christopher A French Saadi Khochbin |
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| Affiliation: | 1. INSERM, U823, Université Joseph Fourier—Grenoble 1, Institut Albert Bonniot, Grenoble, France;2. Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA;3. EMBL Grenoble, Grenoble, France;4. Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA;5. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA;6. Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan |
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| Abstract: | In a subset of poorly differentiated and highly aggressive carcinoma, a chromosomal translocation, t(15;19)(q13;p13), results in an in‐frame fusion of the double bromodomain protein, BRD4, with a testis‐specific protein of unknown function, NUT (nuclear protein in testis). In this study, we show that, after binding to acetylated chromatin through BRD4 bromodomains, the NUT moiety of the fusion protein strongly interacts with and recruits p300, stimulates its catalytic activity, initiating cycles of BRD4–NUT/p300 recruitment and creating transcriptionally inactive hyperacetylated chromatin domains. Using a patient‐derived cell line, we show that p300 sequestration into the BRD4–NUT foci is the principal oncogenic mechanism leading to p53 inactivation. Knockdown of BRD4–NUT released p300 and restored p53‐dependent regulatory mechanisms leading to cell differentiation and apoptosis. This study demonstrates how the off‐context activity of a testis‐specific factor could markedly alter vital cellular functions and significantly contribute to malignant cell transformation. |
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| Keywords: | Brdt cancer testis factor feed forward H3K56 oncogene |
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