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ZRF1 controls oncogene-induced senescence through the INK4-ARF locus

Oncogene volume 32, pages 2161–2168 (2013)Cite this article

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Abstract

The reactivation of the INK4-ARF locus, which is epigenetically repressed by Polycomb proteins in healthy cells, is a hallmark of senescence. One mechanism of reactivating Polycomb-silenced genes is mediated by the epigenetic factor ZRF1, which associates with ubiquitinated histone H2A. We show that cells undergoing senescence following oncogenic Ras expression have increased ZRF1 levels, and that this binds to the p15INK4b, ARF and p16INK4a promoters. Furthermore, ZRF1 depletion in oncogenic Ras-expressing cells restores proliferation by preventing Arf and p16Ink4a expression, consequently bypassing senescence. Thus, ZRF1 regulates the INK4-ARF locus during cellular proliferation and senescence, and alterations in ZRF1 may contribute to tumorigenesis.

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Acknowledgements

We thank VA Raker for help in preparing the manuscript, and to the CRG Genomic Unit. This work was supported by grants from the Spanish ‘Ministerio de Educación y Ciencia’ (CONSOLIDER and BFU2010-18692), from the European Commission FP7 project 4DCellFate (277899), and from AICR (10-0177) to LDC. JDR was supported by grant SFRH/BD/15908/2005 from Foundation for Science and Technology (FCT) Portugal and is a fellow of the Graduate Program in Areas of Basic and Applied Biology (GABBA), University of Oporto, Portugal; LM was supported by a post-doctoral CRG-Novartis fellowship.

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Authors and Affiliations

  1. Department of Differentiation and Cancer, Center for Genomic Regulation (CRG), and Universitat Pompeu Fabra (UPF), Barcelona, Spain

    J D Ribeiro, L Morey, A Mas, A Gutierrez, N M Luis, S Mejetta, H Richly, S A Benitah, W M Keyes & L Di Croce

  2. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain

    S A Benitah & L Di Croce

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  1. J D Ribeiro
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  2. L Morey
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Correspondence to L Di Croce.

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Ribeiro, J., Morey, L., Mas, A. et al. ZRF1 controls oncogene-induced senescence through the INK4-ARF locus. Oncogene 32, 2161–2168 (2013). https://doi.org/10.1038/onc.2012.241

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